Management of patients with systemic vasculitis
Vasculitis is a general term that refers to the inflammation of blood
vessels. When blood vessels become inflamed, they can only react in limited ways.
They may become weakened, stretch and increase in size, or become narrow – even
to the point of closing off entirely.
http://www.coloradoarthritis.com/images/vasculitis.jpg
In an extreme situation, when a
segment of a blood vessel becomes weakened, it may then stretch and bulge
(called an “aneurysm”). The wall of the blood vessel can become so weak that it
ruptures and bleeds. Fortunately, this is a very rare event.
If a blood vessel becomes inflamed
and narrowed, blood supply to that area may be partially or completely
eliminated. If collateral blood vessels (thought of as alternate routes of
blood supply) are not available in sufficient quantity to carry the blood to
such sites, the tissue supplied by the affected blood vessels will die. This is
called infarction.
Because vasculitis can
occur in any part of the body, any tissue or organ can be at risk.
Vasculitis can affect people of all
ages from childhood to adulthood. There are some types of vasculitis that occur
in certain age groups more than others. Vasculitis may occur secondary to an
identified underlying disease or trigger. Occasionally, an allergic reaction to
a medicine may trigger vasculitis. Vasculitis can sometimes develop in
conjunction with an infection. Usually in these cases, the infection causes an
abnormal response in the person’s immune system, damaging the blood vessels.
Viral hepatitis (a type of liver infection), is a specific infection that can
be associated with vasculitis. Vasculitis may also be related to other diseases
of the immune system that the patient had for months or years. For example,
vasculitis could be a complication of rheumatoid arthritis, systemic lupus
erythematosus, or Sjögren’s syndrome. In many cases though, the causes of
vasculitis are not known. These diseases are collectively referred to under the
broad heading of primary forms of vasculitis. In such settings, the appearance
and location of the vasculitis often behaves in a distinct way allowing it to
be diagnosed as a unique type of vasculitis and is given a specific
name.
The vasculitides comprise a heterogeneous group of diseases
characterized by inflammation and destruction of blood vessels. Vessels of any
size can be involved which explains the diverse spectrum of clinical diseases
attributed to vasculitis. While the immunological basis of disease for
vasculitis was recognized over thirty years ago, a standardized classification
system was only adopted nearly twenty years later. The initial classification
system proposed by the American College of Rheumatology attempted to classify
vasculitis according to standardized criteria
Necrotizing
arteritis is common to many forms of vasculitis, but involvement of vessels
smaller than arteries is unique to small vessel vasculitis. A clinical report
of ‘Vasculitis’ originated from the mid-nineteenth century and clinical descriptions of these diseases were
published in the 1930s however it was not until the
1950s that Wegener’s Granulomatosis, Churg Strauss Syndrome and Microscopic
polyangiitis were identified as unique clinical entities. In the 1980s it was appreciated that the small
vessel vasculitides represented a clinically distinct form of disease.
Glomerulonephritis
is a common cause of renal failure both worldwide and in Australia. Rapidly
progressive or crescentic glomerulonephritis represents the most severe form of
the disease and antineutrophil cytoplasmic antibody (ANCA) associated
vasculitis (AAV) accounts for >50% and more likely up to 80% of all cases of
rapidly progressive glomerulonephritis. The AAVs are considered a heterogenous
group of systemic autoimmune conditions characterised by necrotising
inflammation of small to medium sized arteries, capillaries and venules. The
disease is diagnosed by detecting ANCA in the serum which characteristically is
directed against myeloperoxidase (MPO) or proteinase 3 (PR3). The two most
severe clinical manifestations of disease are rapidly progressive
glomerulonephritis and pulmonary haemorrhage due to pulmonary capillaritis.
These syndromes are associated with significant morbidity and untreated have a
mortality that approaches 100%.
The development of autoimmunity is a
complex process, multifactorial in origin, which involves the loss of tolerance
and enhanced cellular and humoral activity.In AAV, disease is defined and
characterized by antibodies detected against MPO or PR3. While antibodies form
the diagnostic hallmark of disease, cellular immunity is critical and is
required for the development of humoral immunity and the subsequent generation
of B cells and production of ANCAs. A role for cellular immunity has been
defined in both clinical and experimental ANCA vasculitis. In addition to
adaptive immune cells, innate immune cells contribute to the generation of
autoimmunity with evidence for involvement of different cell types in this
disease process.
Enhanced cellular autoimmunity and
innate cells stimulate B cells resulting in the production of antigen specific
ANCAs. These auto-antibodies bind to and activate circulating neutrophils.
These activated neutrophils are recruited to glomerular capillaries, where they
degranulate and initiate renal injury. Degranulating neutrophils release their
noxious constituents and also deposit and probably PR3 in the glomerulus.
Later, CD4+ T cells recognise the autoantigen (MPO/PR3) in the glomerulu and
attract additional immune effector cells; this results in severe renal injury.
In both clinical and experimental settings cellular nephritogenic immunity,
humoral immunity and innate immune cells are critical for the development of
rapidly progressive glomerulonephritis. Our current treatment regimes were
designed to target these cells, or combinations of them.
While
we will discuss GPA and MPA separately, there is stronger experimental evidence
linking MPO with disease. This includes several small animal studies which have
confirmed pathogenic roles for cellular and humoral autoimmunity, directed
against MPO, which closely resemble human disease. Our discussion will focus on
the disease pathogenesis of AAV and attempt to define future directions for
study which ultimately may lead to therapeutic interventions. Information has
been made available from human studies assessing mechanisms of disease as well
as experimental studies, utilizing rodent models of vasculitis. Further
insights into disease pathogenesis can be gained from clinical trials,
including those with negative results.Consistent with
improved mechanistic studies the last decade has witnessed significant advances
in our understanding of the role of both the genetic and epigenetic factors
driving AAV. While a detailed description and discussion of these factors is
beyond the scope of this chapter it would be remiss not to discuss several
recent key studies. It is important to note that all results discussed in this
section are from clinical studies. It should also be noted that while the
varying genetic background of commonly used laboratory rodents may contribute
to a particular pattern and severity of disease in experimental AAV, the
relevance and correlation of this to human disease is less clear. These include several genes encoded
in the human leukocyte antigen (HLA) as well as genes encoding protein tyrosine
phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte
antigen 4 (CTLA4), Interleukin (IL)-2, PRTN3 which encodes PR3, α1
anti-trypsin (AAT), complement related genes, CD18, IL-10, CD226 as well as the Fc gamma receptors; FCGR2A, FCGR3B (for both copy number high and copy
number low). For a detailed review of the individual genes linked with clinical
disease, the authors recommend the review by Willcocks and colleagues, whose
work with Ken Smith has been instrumental in advancing knowledge in this field. This is not surprising considering
several of these genes encode proteins critical for maintenance of the immune
system, including the function of innate immune cells, T lymphocytes, B
lymphocytes and regulatory cells. There are several limitations to these
studies. Some studies which linked aberrant gene expression with AAV included
patients with only one form of the disease (i.e. GPA, MPA, RLV or AGA), while
other studies were less specific and included all patients who had detectable
ANCA levels In a genome wide
association study with over 10 000 patients (including controls), not only was
a genetic component confirmed but the antigenic specificity for AAV, i.e. for
MPO or PR3 was found to have distinct genetic associations. For patients with
ANCA directed against PR3, there was a strong genetic association with HLA-DP and genes encoding α1-AT-SERPINA1 and PTN3.
Conversely patients with antibodies directed against MPO showed a strong
association with HLA-DQ.
The observation that there were different genetic associations for MPO-ANCA and
PR3-ANCA strengthens the proposal that these diseases represented two different
clinical entities. Furthermore the stronger genetic component to PR3 related
disease identified in earlier studies was substantiated.
An
epigenetic basis for disease has also been proposed. Neutrophil levels of the
chromatin modification protein complex, H3K27me3, required for gene silencing
were decreased in patients with AAV, at both the MPO and PR3 loci. This
phenomenon was dependent on the transcription factor encoding gene, RUNX3. Interestingly
RUNX3 message was found to be decreased in patients with AAV compared to
healthy controls. In addition to genetic factors, environmental factors
contribute to the loss of tolerance, the development of autoimmunity (to MPO or
PR3) and subsequent organ injury. Environmental triggers that have been
implicated in disease pathogenesis include environmental toxins,
pharmacological therapies and infections, for which there is the strongest
evidence.
Epidemiological studies have demonstrated increased incidence
of ANCA vasculitis, and more specifically MPA, is increased in patients exposed
to a variety of environmental toxins in particular silica. This is thought to
result from environmental toxins serving as adjuvants to the immune system. The
development of ANCAs, in particular those reactive to MPO, is not uncommon
after treatment with propylithiouracil although systemic disease following
treatment is uncommon. Overt MPA with focal necrotising glomerulonephritis has
been described in patients treated with penicillamine and hydralazine. The rarity of these
phenomena has prevented us from learning more about disease pathogenesis.
Links between infection and ANCA vasculitis have been
suggested for some time, with seasonal variation in disease presentation
suggesting a correlation with microbial infection. Moreover results from
several studies suggested that infection(s) may predate disease initiation
and/or relapse in GPA, MPA and pulmonary vasculitis. It must be noted that
these results are contentious and other studies have not confirmed them.
Several
mechanisms have been proposed to link infection with the development of AAV,
including the use of complementary proteins, molecular mimicry and the ligation
of Toll like receptors (TLRs) which heighten innate and adaptive immune
responses as well as activating resident kidney cells. A series of clinical and
experimental studies have supported each of these concepts, however it is
likely that these mechanisms act, at least partially, in combination. Molecular mimicry refers to the
development of antibodies to host proteins after (repeated) exposure to foreign
antigens, this occurs due to structural similarities between host and foreign
proteins. Molecular mimicry has been proposed as a reason for the loss of tolerance
to self and the subsequent development of autoimmunity. In a series of elegant
experiments it was demonstrated that antibodies to the lysosomal associated
membrane protein-2 (LAMP-2) were highly prevalent in patients with ANCA
vasculitis. Furthermore LAMP-2 was pathogenic and administration of polyclonal
LAMP-2 to rodents resulted in a characteristic pattern of AAV, with focal
necrotising glomerulonephritis, similar to that observed in human renal
vasculitis. We will discuss LAMP-
Both
of these studies utilized human samples and elegant rodent models to propose
infections as initiators of autoimmunity and renal vasculitis. Further work in
this field is required to facilitate a better understanding of how molecular
mimicry functions in humans and what organisms could be involved. Infections activate and ligate
Toll-like receptors (TLRs). These receptors are innate pattern and danger
recognition receptors, ubiquitously expressed on immune cells, and resident
tissue cells. which heighten innate and adaptive immune responses in response
to infection or danger signals. Ligation of TLRs after infection can stimulate
host immune responses, promoting auto-inflammatory and auto-immune responses.
Furthermore TLR ligation can stimulate endothelial cells and other resident
kidney cells to generate a cytokine milieu conducive to the recruitment of
inflammatory leukocytes. Since their description in the 1980s
antibodies directed against MPO and PR3 have formed the diagnostic hallmark of
AAV. While not entirely specific there is a strong association between MPO-ANCA
and MPA, while PR3 is commonly associated with GPA. Clinical and experimental
studies have supported the notion that ANCA are pathogenic. Furthermore
therapies targeting (humoral immunity and) ANCAs, including plasma exchange and the anti-CD20 monoclonal antibody
Rituximab, have been successful in clinical practice. Most of the experimental
evidence has supported a role for MPO in disease, but more recently an animal
model of PR3-associated vasculitis has also been developed. This represents a
significant advance and it is anticipated that this model will facilitate an
improved understanding of the pathogenesis of PR3-AAV. In this section, we will
also discuss other roles for B cells including their function as antigen
presenting cells (APCs) and as potential regulators of disease. Animal studies have demonstrated a
pathogenic role for ANCAs. The model described by Xiao et al was one of the
first murine models of AAV, which produced severe renal injury. The observed
renal injury bore considerable resemblance to that seen in human rapidly
progressive glomerulonephritis. In this model MPO deficient mice were immunized
with MPO. Subsequently the spleens of these MPO deficient mice were transferred
into recombinant activation gene knockout (RAG2-/-) mice, which lack adaptive
immunity. After transfer of splenocytes (from MPO immunized MPO-/- mice)
RAG2-/- mice developed humoral autoimmunity with the production of MPO-ANCAs.
Kidneys from these mice displayed the hallmarks of severe crescentic
glomerulonephritis. The authors also performed a passive transfer experiment,
administering MPO-ANCAs to RAG2-/- mice. The passive transfer of MPO-ANCA to
RAG2-/- mice resulted in a milder form of glomerular injury compared to that
seen after splenocyte transferAdditional evidence for a pathogenic role for MPO
in driving AAV and renal injury was demonstrated in Wistar-Kyoto rats. Rats
developed focal necrotizing glomerulonephritis and pulmonary vasculitis after
immunization with purified human MPO. Another potential antigenic target is
LAMP-2. Antibodies to LAMP-2 were reliably detected in more than 90% of
patients with active ANCA associated necrotising crescentic glomerulonephritis.
LAMP-2 antibodies were detected even when MPO-ANCA and PR3-ANCA could not be
detected, suggesting this test may have improved diagnostic sensitivity and
could possibly be useful for serological diagnosis in patients with renal
limited vasculitis, who traditionally are found to be ANCA negative. Antibodies
to LAMP-2 were also pathogenic and administration of human LAMP-2 antibodies to
Wistar Kyoto rats resulted in pauci-immune focal necrotizing
glomerulonephritis. Subsequently, the authors working with several
collaborative groups, have verified the prevalence of antibodies to LAMP-
In vitro studies performed in a flow chamber have shown that
human neutrophils treated with ANCA display altered patterns of rolling,
adhesion and transmigration. Using intravital microscopy to visualise
mesenteric postcapillary venules Little et al found that administration of
MPO-ANCA induced neutrophil adhesion and transmigration. Similarly studies
using intravital microscopy to visualize murine cremasteric postcapillary venules
demonstrated increased neutrophil adhesion and transmigration after the passive
transfer of MPO-ANCA. Neutrophil recruitment was both Fcgamma receptor and
β2 integrin dependent. While these studies provided valuable insight into
neutrophil recruitment and transmigration in inflamed tissues in AAV, it
remained unclear if the observations seen in the postcapillary venules could be
replicated in the glomerulus. The use of live imaging of the murine kidney has
facilitated the study of leukocyte behaviour in models of glomerular injury.
Differences in neutrophil behaviour in the inflamed glomerulus have been noted.
In the heterologous phase of renal injury induced after administration of sheep
anti-mouse GBM serum, neutrophil recruitment occurred via rapid arrest and
occurred in the absence of rolling. Relevant to AAV, in mice treated with LPS
and MPO-ANCA glomerular neutrophil recruitment occurred in a lymphocyte
function-associated antigen (LFA-1)(a leukocyte integrin) dependent manner.
However if an increased dose of MPO-ANCA was used (without LPS priming),
neutrophil recruitment was α4-integrin dependent, but β2-integrin
independent. These studies highlight how MPO-ANCA can induce glomerular
neutrophil recruitment through many different pathways and furthermore
demonstrate that the glomerulus is a unique organ in which neutrophil migration
differs from other postcapillary venules. While it is likely that injury in
humans with renal vasculitis is a consequence of several mechanisms (discussed
above) acting in tandem, direct visualization of the kidney appears to be the
best technique to assess glomerulonephritis. In addition to the mechanisms
detailed above there are likely to be several other factors which contribute to
pathogenic neutrophil-endothelial interaction and the ensuing rapidly
progressive glomerulonephritis, several of these are discussed later in this
chapter.
The
complement system is recognized as one of the phylogenetically oldest
components of human immune defence. This highly regulated system of proteins
(together with their regulatory inhibitors) compromise an important part of
host defence. In response to either innate or adaptive stimuli activation of
the complement system results in a cascade of amplification and cleavage steps
with the generation of anaphylatoxins (C5a and C3a) and a terminal attack
complex capable of lying cells.Three complement pathways are well described,
namely, the classical pathway, the alternate pathway which is initiated by
recognition of foreign surfaces and the mannose binding lectin pathway. More recently a pathway which is
initiated by coagulation and fibrinolytic proteins has been described.In
addition to its role in host defence, activation of the complement cascade can
result in tissue injury and has been implicated in many forms of
glomerulonephritis and kidney injury. Traditionally complement was not
considered critical to the pathogenesis of AAV as renal injury was considered
‘pauci immune’ in nature and hence free from complement (and immune complex)
deposition. Interestingly complement is frequently observed in renal and skin
biopsies from patients with AAV,while in vitro studies have demonstrated a role
for complement in ANCA-neutrophil interactions.
There are
many types of primary vasculitis including disease entities such as Wegener’s
granulomatosis, microscopic polyangiitis, Henoch-Schönlein purpura,
polyarteritis nodosa, Kawasaki disease, giant cell arteritis, Takayasu’s
arteritis, and Behçet’s disease. Some are named after doctors (Wegener,
Takayasu, Kawasaki) who were among those to provide the best original
descriptions of the illness or are named based on features seen on biopsies
(giant cell arteritis, angiitis, arteritis nodosa) of affected tissues or blood
vessels. Although most of these are systemic (or generalized) vasculitides
where the vasculitis may affect many organ systems at the same time, they often
differ a great deal among each other. Some of the primary systemic vasculitic
diseases may be quite mild and require little or even no treatment. Other forms
may be severe, affecting critical organs and, if left untreated, may lead to
death within days or months. Some forms of primary vasculitis may be restricted
in their location to certain organs (these are called isolated forms of
vasculitis). Examples include vasculitis that only occurs either in the skin,
eye, brain (isolated CNS vasculitis) or certain internal organs. Because any organ system may be
involved, an enormous number of symptoms are possible. If the skin is involved,
there may be a rash. If nerves suffer loss of blood supply, there may initially
be an abnormal sensation followed by a loss of sensation. Vasculitis in the
brain may cause a stroke, or in the heart may result in a heart attack. Kidney
inflammation usually is not associated with symptoms and is detected by the
doctor by examination of the urine. This is important to recognize as
inflammation in the kidneys can lead to kidney failure unless promptly
detected. Sometimes the symptoms are nonspecific. When inflammation is present
in the body, we tend to respond in ways that tell us that we are not well, but
those responses may not be unique to vasculitis at all. For example, along with
the symptoms mentioned previously, a person with vasculitis may also have a
fever or experience loss of appetite, weight loss and loss of energy.
Treatment depends entirely upon the
diagnosis, the organs that are affected, and the severity of the vasculitis.
When vasculitis represents an allergic reaction, it may be “self limiting,” or
will go away on its own and not require treatment. There are other instances also
where minimal to no treatment is required and the person can be closely
observed. In instances
where critical organs such as the lungs, brain or kidneys are involved, the
outlook is less positive and aggressive and timely treatment is necessary. For
most forms of systemic vasculitis, treatment generally includes corticosteroid
medications (prednisone is the most commonly prescribed). For some forms of
vasculitis, treatment must also include another immunosuppressive medication
used in combination with the prednisone. Some of these medications are
chemotherapy agents like those used to treat cancer, but are given in doses
considerably lower than people with cancer may receive. The goal of this type
of chemotherapy is to suppress the abnormal immune response that has led to
blood vessel damage.
The outlook
for a person who has vasculitis will vary with the type of vasculitis that is
present, what organs are being affected, how severe the vasculitis is, and how
the person responds to treatment. Knowing the type of vasculitis allows the
doctor to predict the likelihood of illness severity and outcome.
Prior to the time of available
treatment, people with severe vasculitis may have had anticipated survival of
only weeks to months. However, today with proper treatment, normal life spans
are possible. The success of therapy is related to prompt diagnosis, aggressive
treatment and careful follow-up to be sure that side effects from medications
do not develop.
Once
vasculitis is under control (often referred to as “remission”), medications may
be cautiously withdrawn, with the hope that the patient will sustain a long
remission, independent of treatment. Because some forms of vasculitis can recur
(referred to as a “relapse”) after a period of remission, it is very important
for patients with vasculitis to remain under the care of a knowledgeable
physician.
Vasculitis is characterized by
inflammation in blood vessel walls
Systemic vasculitis, of course, as we are all aware, is a rather complex issue.
Obviously in 30 minutes it is going to be difficult to really discuss this in
great depth.
|
Necrotizing
arteritis in a skeletal muscle biopsy. Note the segmental transmural necrosis
and inflammation with an adjacent thrombus. |
|
It is not inflammation around
vessels; it is inflammation of vessel walls. The vasculitis that affect the
kidney most often are necrotizing vasculitides that affect parenchymal arteries
and also in fact very often vessels other than arteries. You could say vessels
smaller than arteries, but it's really more definitive to say vessels other
than arteries. Today we are really going to be concerned with necrotizing
vasculitis affecting arteries and other smaller vessels.
Large vessel disease
There are large vessel vasculitides that occasionally affect the kidney. These
vasculitides by definition affect the aorta and its major branches; and
therefore, the major impact on the kidney is through the induction of
hypertension.
Medium and small vessel vasculitides
Really the more difficult classification and therefore diagnostic problems are
with vessels that affect the parenchymal arteries, arterioles, the glomerular
capillaries and even other vascular structures, such as the vasa recta within
the kidney. So we are going to be concerned with these so-called medium-sized
vessel vasculitides, which, by at least the definition at I prefer, indicates
that they involve arteries; and small-vessel vasculitides, which means that
they involve vessels other than arteries, which of course means vessels smaller
than arteries, such as capillaries and venules.
Some of the earliest investigations
of patients with vasculitis were prompted by the recognition of arteritis,
which in fact could be seen grossly as modular enlargements in the arteries
within the parenchyma and even in main visceral arteries such as the renal
arteries, hepatic artery. There were many early reports. Certainly Karl
Rokitansky described patients with what was in fact arteritis in his
discussions of patients with aneurysms. But Kussmaul and Maier in 1866 really
published one of the first detailed descriptions of vasculitis in patients. In
the one patient that they described most carefully, the involvement was
predominantly, at least, within arteries and could be seen grossly; but
microscopically, it involved very small vascular radicals as well.
In their
patient the presentation was similar to what I'm sure you've seen in your own
patients. There were the non-specific manifestations of a systemic inflammatory
process--fever, anorexia, weakness. There were also indications of vascular
involvement in the tissues--myalgia, paresthesia, abdominal pain, cutaneous
nodules, and there was oliguria. The gross pathology, as I mentioned and, as
was illustrated here in the article by Kussmaul and Maier, was predominantly
nodular thickenings along arterial radicals. Histologically this was shown to
be inflammation and necrosis.
|
Renal
involvement by polyarteritis nodosa. Note dark thrombosed pseudoaneurysms and
pale peripheral infarcts. |
|
Gross changes of
medium-sized vessel vasculitis
This is a similar presentation to what was seen and illustrated by Kussmaul and
Maier. In this photograph, you can see that these kidneys have large aneurysms
filled with clotted blood. These are really not true aneurysms; they are
pseudo- aneurysms because actually the inflammatory process has eroded through
the vessel wall and into the adjacent parenchyma. So it's not just a dilation
of a vessel--it's an erosion through a vessel by this necrotizing process. Of
course, this process can occlude the arterial arteries that are involved. You
can see in the periphery here a number of infarcts, which is a complication of
arteritis affecting the larger vessels in the kidney. In fact, there was
rupture of one of the aneurysms. This patient actually died from massive
hemorrhage into the retroperitoneal and peritoneal cavities. In this patient
you can also see the typical nodular inflammatory lesion of polyarteritis
nodosa as it's called today.
Polyarteritis nodosa
Polyarteritis
nodosa (PAN or c-PAN) is a systemic vasculitis
characterized by necrotizing inflammatory lesions that affect medium-sized and
small muscular arteries, preferentially at vessel bifurcations, resulting in
microaneurysm formation, aneurysmal rupture with hemorrhage, thrombosis, and,
consequently, organ ischemia or infarction.
Hystory
Kussmaul and Maier first described PAN in 1866. The autopsy of a patient
with fever, weight loss, abdominal pain, and polyneuropathy revealed areas of
focal inflammatory exudations that gave rise to palpable nodules along the
course of medium-sized arteries.PAN, like other vasculitides, affects multiple
systems and has protean manifestations, although it most commonly affects skin,
joints, peripheral nerves, the gut, and the kidney. The lungs are usually
spared with PAN. A typical PAN patient might present with fever, night sweats,
weight loss, skin ulcerations or tender nodules, and severe muscle and joint
pains developing over weeks or months.
Epidemiology
Occurrence
Polyarteritis nodosa (PAN) is a rare disease, with an incidence of about
3-4.5 cases per 100,000 population annually. Older estimates placed the
prevalence as high as 7.7 cases per 100,000 population,
for example, in a population of Alaskan Eskimos hyperendemic for HBV infection.
International
occurrence
Depending on the definitions used, the annual estimated incidence of PAN
ranges from 1.6 cases per million in south
Sex-
and age-related demographics
PAN affects men more frequently than women (male-to-female ratio
1.6-2:1). PAN has been diagnosed in persons of every age; however, it is
predominantly observed in individuals aged approximately 45-65 years.
Causes and risk factors
Polyarteritis nodosa is a disease of unknown cause
that affects arteries, the blood vessels that carry oxygenated blood to organs
and tissues. It occurs when certain immune cells attack the affected arteries.
One hypothesis is that this condition is caused by antibodies against HBV
(Hepatitis B Virus), via a type III hypersensitivity reaction
Hepatitis
B and PAN
The pathogenesis of polyarteritis nodosa (PAN) is
unknown, and no animal model is available for study. Viral infections,
including human immunodeficiency virus (HIV) infection, hepatitis C
virus (HCV) infection and, most strongly, hepatitis
B virus (HBV) infection, have been associated with PAN. Evidence for
immune complex–induced disease is confined to HBV-related PAN; the role of
immune complexes in non–HBV-related PAN remains unclear. Impaired function of
endothelial cells may be part of idiopathic PAN or a consequence of it; in
HBV-PAN, virus replication may directly injure the vessel wall. Endothelial
dysfunction can perpetuate the inflammation through cytokine and adhesion
molecule production.
HBV was once the cause of up to 30% of PAN cases. Widespread
use of the hepatitis B vaccine has significantly decreased the incidence of
HBV-PAN, which is now estimated to account for less than 8% of all PAN cases.
HBV-associated vasculitis almost always takes the
form of PAN. HBV-PAN may occur at any time during the course of acute or
chronic hepatitis B infection, although it typically occurs within 6 months of
infection.
The activity of the arteritis does not parallel
that of the hepatitis, and symptoms are the same as those of idiopathic PAN.
Small studies have found that GI manifestations, malignant hypertension, renal
infarction, and orchiepididymitis were more common in HBV-PAN.
Other disease associations
Other
infectious organisms have been reported in association with PAN or PAN–like
diseases, but causal evidence is inconsistent. These organisms include
varicella-zoster virus, parvovirus B-19, cytomegalovirus, human T-cell leukemia, virus,streptococcalspecies, Klebsiella species, Pseudomonas species, Yersiniaspecies, Toxoplasma
gondii, Rickettsiae, trichinosis, and sarcosporidiosis.
Hepatitis C may be linked to cutaneous PAN, a benign, limited form of
PAN. In a study of 16 patients with cutaneous PAN, 5 tested positive for
hepatitis C.
Some syndromes, including rheumatic diseases, malignancies, and
infections have been associated with clinical syndromes indistinguishable from
idiopathic PAN. Rheumatoid arthritis (RA) and Sjögren
syndrome have been associated with PAN. Notably, the incidence of
RA-associated vasculitis has decreased greatly since the 1980s, likely
attributable to improvements in the management of RA.
Hematologic
malignancies, such as hairy cell leukemia, have been associated with PAN–like
vasculitides.
Microscopic changes in the pancreas:
polyarteritis nodosa. Here we can
see an artery within the pancreas. At this point the walls have been eroded
through and there is this large pseudo-aneurysm filled with thrombotic material.
This process was initially called periarteritis nodosa by Kussmaul and
Maier, but soon after the term polyarteritis nodosa became more popular,
and nowadays it is really the preferred term because many different vessels are
involved and it is really a transmural process, not a perivascular process.
It is found that some vasculitis has
granulomatous changes.
For over 50 years almost anyone with necrotizing arteritis was called
periarteritis nodosa or polyarteritis nodosa. Anybody with necrotizing arteritis
was put into that category. But by the 30s, it was becoming clear that there
were various patients who had distinctive features in addition to the systemic
necrotizing vasculitis that warranted separation into a different category.
Polyarteritis
nodosa (or periarteritis nodosa) is a vasculitis of
medium-sized arteries, which become swollen and damaged from attack by rogue
immune cells. Polyarteritis nodosa is also called Kussmaul disease.
Systemic necrotizing inflammation of
medium-sized and small muscular arteries. More common in adult males. Spares the arterioles, capillaries,
venules and glomeruli
Associated with hepatitis B antigenemia.
Symptoms
PAN is
a multisystem disease that may present with fever, sweats, weight loss, and
severe muscle and joint aches/pains. PAN may develop in a subacute fashion,
over several weeks or months.
Polyarteritis nodosa (PAN) is an acute
multisystem disease with a relatively short prodrome (ie, weeks to months).
Delays in diagnosis are not uncommon. The spectrum of disease ranges from
single-organ involvement to fulminant polyvisceral failure. Pertinent and
common historical features of PAN include the following:
Constitutional and musculoskeletal
symptoms
Constitutional and musculoskeletal symptoms of
PAN include the following:
- Fever
- Malaise
- Fatigue
- Anorexia
and weight loss
- Myalgia
- Arthralgia
in large joints or, less commonly, arthritis
Central nervous system symptoms
Transient symptoms of cerebral ischemia,
including typical spells of transient monocular blindness, are the most common
presenting CNS deficits of PAN. Cerebral arteritis usually presents late in the
course of the disease, usually in the second to third year of the vasculitis.
Cerebral arteritis may cause arterial thrombosis with cerebral ischemia or intraparenchymal
or subarachnoid hemorrhage.
Global CNS dysfunction with encephalopathy and
seizures results from metabolic derangements secondary to multiple organ
failure. Acute or subacute myelopathy with paraparesis can occur at any cord
level. Myelopathy may result, although rarely, from cord compression by an
extramedullary hematoma secondary to a ruptured spinal aneurysm. Although CNS
lesions usually occur 2-3 years after the onset of PAN, earlier CNS involvement
has been reported.
Peripheral nervous system symptoms
Peripheral neuropathy develops in as many as 60%
of patients. Vasculitic neuropathy is often asymmetrical and presents as (1)
mononeuritis multiplex, (2) distal polyneuropathy, or (3) cutaneous neuropathy.
It can take the form of a pure motor, pure sensory, or mixed sensorimotor
polyneuropathy.
Cutaneous symptoms
Dermatologic symptoms are very common in PAN, and
about 40% of patients manifest with skin lesions including rash, purpura,
gangrene, nodules, cutaneous infarcts, livido reticularis, and Raynaud
phenomenon. Skin involvement, which can be painful, occurs most frequently on
the legs.
Cutaneous symptoms in PAN include the following
(see the images below):
1.
Livedo reticularis that does not
blanch with active pressure
2.
Ulcerations - Especially on the lower
extremities, near the malleoli and on the calf
3.
Digital ischemia - May be accompanied
by splinter hemorrhages and, sometimes, gangrene
4.
Nodules - Usually on the lower
extremities (like ulcers); nodules are the least common skin manifestation of
PAN
http://diseasespictures.com/polyarteritis-nodosa/
http://igorbogdanov.org/publ/medicina/revmatologija/uzelkovyj_periarteriit/16-1-0-55
Livedo
reticularis
Skin abnormalities are
very common in PAN and may include purpura, livedo reticularis, ulcers, nodules
or gangrene.
Skin involvement occurs
most often on the legs and is very painful.
Cutaneous polyarteritis nodosa presents
with tender erythematous nodules on the lower legs that often ulcerate The
involved area usually shows livedo reticularis.
Gastrointestinal symptoms
GI involvement usually presents as nonspecific symptoms and signs such
as abdominal pain (which may be postprandial) and nausea and vomiting, with or
without obvious GI bleeding. Rare and more serious complications of PAN include
bowel infarction and perforation, cholecystitis, hepatic infarction, or
pancreatic infarction. Gastrointestinal symptoms include the
following:
- Tender abdomen with or
without rigidity, guarding, or diminished bowel sounds
- GI bleeding
- Bowel infarction
- Cholecystitis
Renal symptoms
About 60% of patients with PAN have renal
involvement. Flank pain may be present. Ischemic changes in the glomeruli and
renal artery vasculitis can cause renal failure, hypertension, or both. A small
percentage of patients may require dialysis.
Additional symptoms
- Less common symptoms
reported in PAN include the following:
- Genitourinary - Patients
may develop pain over the testicular or ovarian area. In rare cases,
testicular infarction may occur; testicular pain is usually unilateral
- Cardiac - Chest pain,
dyspnea, palpitations, pericarditis, myocardial infarction, and congestive
heart failure; cardiac disease affects 35% of patients with PAN, but most
affected patients are asymptomatic
- Ophthalmologic - Blurred
vision
- Neuropsychiatric -
Headache, psychosis, and depression
Kidney
-Renal artery vasculitis may lead to
protein in the urine, impaired kidney function, and hypertension.
-Small percentage of patients go on
to require dialysis.
Gastrointestinal
Tract
-Abdominal pain, gastrointestinal
bleeding (occasionally is mistaken for inflammatory bowel disease)
-Hemorrhage, bowel infarction, and
perforation are rare, but very serious
Heart
-Clinical involvement of the heart
does not usually cause symptoms.
-However, some patients develop
myocardial infarctions (heart attacks) or congestive heart failure.
Eye
-Scleritis or inflammation in the
sclera (white part of the eye)
Genitals
-Testicular infarction
In this
disease, symptoms result from ischaemic damage to affected organs, often the
skin, heart, kidneys, and nervous system.
Generalised
symptoms include fever, fatigue, weakness, loss of appetite, and weight loss.
Muscle and joint aches are common. The skin may show rashes, swelling, ulcers,
and lumps. Nerve involvement may cause sensory changes with numbness, pain,
burning, and weakness. Central nervous system involvement may cause strokes or
seizures. Kidney involvement can produce varying degrees of renal failure.
Involvement
of the arteries of the heart may cause a heart attack, heart failure, and
inflammation of the sac around the heart (pericarditis).
- Fatigue
- Weakness
- Fever
- Abdominal pain
- Decreased appetite
- Unintentional weight loss
- Muscle aches
- Joint aches
Diagnostic criteria
A patient is
said to have polyarteritis nodosa if he or she has 3 of the 10 following signs
known as:
The 1990 ACR (American College of Rheumatology)
criteria:
- Weight loss greater
than/equal to
- Livedo reticularis (a
mottled purplish skin discoloration over the extremities or torso).
- Testicular pain or
tenderness. (occasionally, a site biopsied for
diagnosis).
- Muscle pain, weakness, or
leg tenderness.
- Nerve disease (either single
or multiple).
- Diastolic blood pressure
greater than 90mmHg (high blood pressure).
- Elevated kidney blood tests
(BUN greater than 40 mg/dl or creatinine greater than 1.5 mg/dl).
- Hepatitis B virus tests
positive (for surface antigen or antibody).
- Arteriogram (angiogram)
showing the arteries that are dilated (aneurysms) or constricted by the
blood vessel inflammation.
- Biopsy of tissue showing the
arteritis (typically inflamed arteries).
It should be underlined that the 1990
ACR criteria were designed for classification purposes only. Nevertheless their
good discriminatory performances, indicated by the initial ACR analysis,
suggested their potential usefulness for diagnostic purposes also. Subsequent
studies did not confirmed their diagnostic utility, demonstrating a significant
dependence of their discriminant abilities on the prevalence of the various
vasculitides in the analyzed populations. Recently an original study, combining
the analysis of more than 100 items used to describe patients characteristics
in a large sample of vasculitides with a computer simulation technique designed
to test the potential diagnostic utility of the various criteria, proposed a
set of eight positively or negatively PAN discriminating items to be used a
screening tool for PAN diagnosis in patients suspected of systemic vasculitis.
Laboratory Investigations
1.
Hepatitis B surface antigen is +ve in 30%.
2.
p-ANCA is usually +ve, but not pathognomic.
3.
ESR is raised.
4.
FBC shows leukocytosis with raised neutrophils.
5.
Hypergammaglobulinaemia occurs in 30%.
Angiography
Angiography should be considered if clinically involved tissue is
inaccessible. Conventional angiography is preferred. Computed tomography
angiography or magnetic resonance angiography are not as sensitive for smaller
abnormalities but can reveal larger aneurysms and stenoses.
Positive findings include aneurysms and stenoses of medium-sized
vessels. (Note that these findings are not pathognomonic for PAN but rarely
occur in MPA).
Aneurysms
are most commonly found in the kidney, liver, and mesenteric arteries, and
their presence is associated with more severe and extensive disease.
Angiography has a higher yield in cases with evidence of intra-abdominal
involvement, including clinical symptoms or signs and laboratory abnormalities
of liver or renal function.
Electromyography (EMG) and nerve conduction studies (NCS) can be useful
in revealing axonal nerve involvement and identifying asymmetry in nerve
involvement. EMG/NCS can be used to guide a nerve biopsy, if necessary.
Other
studies
Arteriograms reveal microaneurysms in the small- and medium-sized
arteries of the kidneys and abdominal viscera.
Computed tomography (CT) scanning and magnetic resonance imaging (MRI)
of the GI tract may show nonspecific abnormal findings, including bowel wall
thickening, mesenteric vascular engorgement, ascites, bowel obstruction, or
diffuse mucosal fold thickening. For PAN with CNS involvement, new techniques,
including susceptibility for blood, diffusion, and perfusion-weighted images,
make MRI a very powerful modality for differentiating intracranial hemorrhage
from potentially reversible ischemia (since PAN lesions are typically
irreversible and progressive).
Biopsy
When
possible, a biopsy sample of involved, accessible tissue should be collected to
aid in the diagnosis. The most accessible tissue sites for biopsy include the
skin, sural nerve, testes, and skeletal muscle. The results of a retrospective
study suggest muscle biopsy may be helpful for the diagnosis of systemic
vasculitides, even in the absence of myalgias or creatine kinase level
elevation. Kidney biopsy carries a risk of aneurysmal rupture and
bleeding.
Biopsies should be performed correctly to allow for adequate sampling of
medium-sized arteries. Biopsy samples of skin nodules or ulcers should be
collected at the edges and include deep dermis and subcutaneous fat.
In addition, nearby central ulcer areas, including subcutaneous tissue, should
be included to increase diagnostic yield.
Biopsy
of small arteries from the abdominal viscera in conjunction with arteriography
facilitates identification of the vasculitis.
Combined
nerve and muscle biopsy is preferred. Biopsy of the sural nerve should be
full-thickness to include epineural vessels.
Histologic
Findings
Histology reveals a focal necrotizing arteritis of generally mixed
cellular infiltrate within the vessel wall. Nerve biopsy characteristically
reveals axonal degeneration and fiber loss. Segmental demyelination may also be
seen.
When
an inflammatory infiltrate is present around a vessel wall without necrotizing
changes, features on nerve biopsy that strongly suggest angiopathic nerve
injury include Wallerian degeneration and fiber loss in part of a fascicle,
perineural necrosis, and neoangiogenesis around the epineurium or perineurium.
Histopathologic
features of cutaneous polyarteritis nodosa.
Scanning power shows sparse inflammatory
infiltrate in the subcutis.
Higher magnification shows the
inflammatory infiltrate centered in a blood vessel.
Still higher magnification shows an
eosinophilic ring of fibrinoid necrosis at the tunica intima of the involved
blood vessel.
Still higher magnification of the
eosinophilic ring of fibrinoid necrosis giving a targetlike appearance to the
vessel.
Treatment
The treatment includes three phases: induction of remission, maintenance, and treatment of relapse. The severity and extent of the disease divides patients into three groups: those with localized or early disease, those with generalized disease with threatened organ involvement, and those with severe or life-threatening disease. For patients with localized and early disease, treatment with steroids and methotrexate or cyclophosphamide is recommended for induction of remission. Methotrexate may be associated with a higher relapse rate. Evidence of relapse or disease progression despite treatment with methotrexate requires the use of cyclophosphamide. Initial treatment of generalized organ-threatening disease should include steroids and cyclophosphamide. Cyclophosphamide can be administered as an intravenous infusion every two weeks (and later every three weeks), or as a daily low-dose oral treatment. There is no difference in remission rates or relapse risk between oral and intravenous regimens. Steroids are given as daily oral prednisone (1 mg per kg, up to 60 mg daily). Pulsed intravenous steroids can be given just before or with the first two intravenous pulses of cyclophosphamide. Patients presenting with severe life-threatening disease (severe renal failure or pulmonary hemorrhage) should be treated with cyclophosphamide (pulsed intravenous or continuous oral) and steroids, with adjuvant plasma exchange.
Maintenance therapy with either azathioprine
or methotrexate is initiated if remission has occurred after three to six
months of induction therapy. Steroid dosage is tapered during this phase.
Patients may need to continue maintenance treatment for up to 24 months. Maintenance treatment for up to five
years is recommended in patients who remain ANCA-positive. Some patients may require treatment
indefinitely. Disease relapse may occur anytime after the remission. Serial
measurements of ANCA are not closely associated with disease activity;
therefore, treatment should not be solely guided on the basis of an increase in
ANCA. Relapsing disease can be managed with an increase in steroid dose,
optimization of the current immunosuppressant, or combination of an
immunosuppressant with an increased dose of steroid.
Novel
biologic therapies targeted against specific components of the immune system
are being used for systemic vasculitis, particularly for patients in whom conventional
therapy has failed. Agents such as infliximab (Remicade; human chimeric
anti-tumor necrosis factor [TNF]-α monoclonal antibody), etanercept
(Enbrel; fusion protein of the p75 TNF-α receptor and immunoglobulin G1),
adalimumab (Humira; fully humanized IgG1 anti-TNF-α monoclonal antibody),
rituximab (Rituxan; anti-CD20 chimeric mouse/human monoclonal antibody),
anakinra (Kineret; recombinant interleukin-1 receptor antagonist), and
intravenous immune globulins may be used in refractory disease.
Patients with systemic vasculitis are at increased risk of comorbidities
resulting from disease-related end organ damage and immunosuppressive therapy.
The immunosuppressive medications used for the treatment of systemic vasculitis
cause serious adverse effects during the first year of therapy. Steroids and
cyclophosphamide predispose patients to life-threatening infections.
Cyclophosphamide can cause hemorrhagic cystitis, ovarian and testicular
failure, and bladder cancer. Diagnosis and treatment of these complications are
coordinated with the family physician. Recommendations regarding detecting and
preventing these complications include use of mesna (Mesnex) for protecting
against urothelial toxicity of cyclophosphamide, antifungal prophylaxis,
prophylaxis against Pneumocystis jiroveci, consideration for Staphylococcus
aureus treatment,
screening for cervical malignancy, and counseling about infertility with
cyclophosphamide. Adverse effects of long-term steroid use (e.g., diabetes
mellitus, osteoporosis, cataract) should be assessed. Vitamin D and calcium
prophylaxis are recommended in patients on long-term therapy with steroids.
Management of systemic vasculitis is complicated. Educating patients
about signs and symptoms, and monitoring typical adverse effects are helpful.
Many patients will have a relatively benign, self-limited course, especially if
the disease is limited to the skin; however, for patients with aggressive
disease, such as ANCA-associated small vessel vasculitis, it is imperative to
begin treatment without delay. The multisystem involvement in systemic
vasculitis necessitates a multidisciplinary team approach to patient care.
Recent advances in therapy have led to considerably better outcomes in patients
with vasculitis.
Complications
Without treatment, hypertension
induced glomerulonephritis was the cause of great morbidity and mortality.
Other complications include:stroke, encephalopathy, myelopathy, heart attack, myocardial infarction, pericarditis, renal failure, GI bleeding, pancreatitis, intestinal
necrosis and perforation, peripheral neuropathy, gangrene of digits.
Prognosis
Without treatment, almost
half will die within three months of diagnosis, the majority as a result of
renal failure and the 5 year survival is in the order of 13%. In a large study
of early deaths,13 58% were caused by uncontrolled vasculitis and 26% by
infection. Treatment had less effect on early mortality.
Poor prognostic features included,
being older, renal involvement, CNS involvement and a trend towards cardiomyopathy. Corticosteroid treatment improves the
5-year survival rate to 50 to 60%. In combination with other
immunosuppressants, the 5-year survival rate is in excess of 80%.
Prevention
This disease cannot be currently prevented, but early
treatment can prevent some damage and symptoms.
Henoch-Schonlein purpura
Willan and Heberden
appeared to have first noted Henoch-Schoenlein (or Henoch-Schönlein)
purpura (HSP) in the early 1800s. However, Schönlein first described the
combination of acute purpura and arthritis in children in 1837, and
Henoch reported the manifestations of abdominal pain and nephritis in
1874.
Henoch-Schoenlein purpura is an acute
immunoglobulin A (IgA)–mediated leukocytoclastic vasculitis that primarily
affects children. The dominant clinical features of Henoch-Schoenlein purpura
include cutaneous purpura, arthritis, abdominal pain, GI bleeding, orchitis,
and nephritis.
Epidemiplpgy
The prevalence of
Henoch-Schoenlein purpura peaks 3-10% in population. In the Northern
hemisphere, the disease occurs mostly from November to January. The
male-to-female ratio is 1.5-2:1. In one half to two thirds, an upper
respiratory tract infection precedes the clinical onset of Henoch-Schoenlein
purpura by 1-3 weeks. In general, patients with Henoch-Schoenlein purpura
appear mildly ill. They often have a fever, with a temperature usually not
higher than
Causes
Henoch-Schonlein
is caused by an abnormal response of the immune system. It is unclear why this
occurs. The syndrome is
usually seen in children, but it may affect people of any age. It is more
common in boys than in girls. Many people with Henoch-Schonlein purpura had an
upper respiratory illness in the weeks before.
The conditions below may precede Henoch-Schoenlein purpura.
Infections include the following:
·
Mononucleosis
·
Group A streptococcal infection (most common)
·
Hepatitis
·
Mycoplasma infection
·
EBV infection
·
Varicella-zoster viral infection
·
Parvovirus B19 infection
·
Campylobacter enteritis
·
Hepatitis C–related liver cirrhosis
·
Subacute bacterial endocarditis
·
Helicobacter pylori infection
·
Yersinia infection
·
Shigella infection
·
Salmonella infection
·
Brucellosis
Vaccinations
include the following:
·
Typhoid
·
Measles
·
Cholera
·
Yellow fever
Environmental
exposure to allergens include the following:
·
Drugs (eg, ampicillin, erythromycin, penicillin,
quinidine, quinine, cytarabine)
·
Foods
·
Horse serum
·
Cold exposure
·
Insect bites
Glomerulocystic
kidney disease has also been noted.
Pathophysiology
The etiology of Henoch-Schoenlein purpura
remains unknown. However, IgA clearly plays a critical role in the
immunopathogenesis of Henoch-Schoenlein purpura, as evidenced by increased
serum IgA concentrations, IgA-containing circulating immune complexes, and IgA
deposition in vessel walls and renal mesangium. Henoch-Schoenlein purpura is
almost exclusively associated with abnormalities involving IgA1, rather than
IgA2.
The predominance of IgA1 in Henoch-Schoenlein
purpura may be a consequence of abnormal glycosylation of O-linked
oligosaccharides unique to the hinge region of IgA1 molecules. Although several
lines of evidence suggest a genetic susceptibility to Henoch-Schoenlein purpura,
the fundamental basis for this abnormality remains unclear. IgA aggregates or
IgA complexes with complement deposited in target organs, resulting in
elaboration of inflammatory mediators, including vascular prostaglandins such
as prostacyclin, may play a central role in the pathogenesis of
Henoch-Schoenlein purpura vasculitis.
A subpopulation of human lymphocytes bears surface Fc and/or C3 receptors
(complement receptor lymphocytes), which can bind circulating immune complexes
or C3 generated by activation of the alternative complement pathway. Such
immune complexes appear in Henoch-Schoenlein purpura and may be part of the
pathogenetic mechanism.
Some have speculated that an antigen stimulates the production of IgA,
which, in turn, causes the vasculitis. Allergens, such as foods, horse serum,
insect bites, exposure to cold, and drugs (eg, ampicillin, erythromycin,
penicillin, quinidine, quinine), may precipitate the illness. Infectious causes
include bacteria (eg,Haemophilus, Parainfluenzae, Mycoplasma, Legionella,
Yersinia, Shigella, orSalmonella species) and viruses (eg,
adenoviruses, Epstein-Barr virus [EBV], parvoviruses, varicella).
Vaccines such as those against cholera, measles, paratyphoid A and B, typhoid,
and yellow fever have also been implicated. Evidence supporting a direct role
of herpesvirus, retrovirus, or parvovirus infection in Henoch-Schoenlein
purpura is lacking.
Alterations in the production of interleukins (ILs) and growth factors
may also have a role in the pathogenesis of Henoch-Schoenlein purpura. Tumor
necrosis factor (TNF), IL-1, and IL-6 may mediate the inflammatory process
present in Henoch-Schoenlein purpura. Transforming growth factor–beta
(TGF-beta), is a recognized stimulant of IgA production. The elevated levels of
hepatocyte growth factor present during the acute phase of Henoch-Schoenlein
purpura may reflect endothelial-cell damage or dysfunction. Increased levels of
vascular endothelial growth factor may at least partly induce these changes.
Cytokines have been implicated in the pathogenesis of Henoch-Schoenlein
purpura, and endothelins (ETs), which are vasoconstrictor hormones produced by
endothelial cells, may also have a role. levels of ET-1 are substantially
higher during the acute phase of the disease than during remission or in a
control group of children. However, ET-1 levels do not appear to be correlated
with morbidity, severity of disease, or acute-phase reactant response.
A
functional correlation of the IL1RN-2 allele and IL-1ra
production in patients with IgA nephropathy and Henoch-Schoenlein purpura
nephritis (HSPN) has been described. Therefore, gene polymorphism may
contribute to the diversity of clinical responses to inflammatory stimulation.
Emerging
data
Results support a role of human leukocyte antigen (HLA)–B35 in the
susceptibility to nephritis in unselected patients with Henoch-Schoenlein
purpura.
Researchers
are currently investigating the importance of nitric oxide (NO) production in
disease activity. Inducible NO synthase polymorphism is associated with
susceptibility to Henoch-Schoenlein purpura in northwestern Spain
The
prevalence of the human parvovirus B19 component NS1 gene in
patients with Henoch-Schoenlein purpura and hypersensitivity vasculitis is
increased.
Henoch-Schoenlein
purpura that is likely due to montelukast has been noted in patients who
present with subacute intestinal obstruction.
Clinic
Scrotal involvement is not uncommon in
Henoch-Schoenlein purpura and may mimic testicular torsion, which must be
excluded. Male patients may have associated inflammation and hemorrhage of the
testes, appendix testes, spermatic cord, epididymis, or scrotal wall. True
torsion is rare. Ha and Lee reported that neurologic symptoms, localized edema,
and high serum C3 levels have a significant relationship with scrotal
involvement in male patients with Henoch-Schoenlein purpura.
GI symptoms can accompany the onset of
Henoch-Schoenlein purpura or may develop later in the course of disease.
Abdominal pain occurs in 35-85% of patients and is the third most common
presenting symptom in Henoch-Schoenlein purpura. GI problems usually follow the
onset of rash and joint pain. Multiple and recurrent intestinal perforations
are an unusual complication of Henoch-Schoenlein purpura. In addition to
abdominal pain, GI findings can include the following:
·
Nausea
·
Vomiting
·
Diarrhea with
gross or occult blood
·
Hematemesis
·
Intussusception:
This occurs in 2-3% of patients, and the lead point
can be a submucosal hematoma.
·
Bowel
infarction with or without perforation
·
Ileal
stricture
·
Ileus
with massive GI bleed
·
Acute
appendicitis
Arthralgias occur in 60-84% of patients with Henoch-Schoenlein purpura and most commonly affect the knees, ankles, and, less frequently, the wrists and fingers. True arthritis does not occur, and joint effusions are rare. Henoch-Schoenlein purpura leaves no permanent joint deformities. Henoch-Schonlein is a type of hypersensitivity vasculitis and inflammatory response within the blood vessel. It is caused by an abnormal response of the immune system. The exact cause for this disorder is unknown.
Purpura
of the skin is the most prominent physical finding in
Henoch-Schoenlein purpura, but renal, GI, and joint manifestations are commonly
present. Other manifestations have also been reported.
Henoch-Schoenlein purpura begins with a
symmetrical erythematous macular rash on the lower extremities that quickly
evolves into purpura. The rash may initially be confined to malleolar skin but
usually extends to the dorsal surface of the legs, the buttocks, and the ulnar
side of the arms. Within 12-24 hours, the macules evolve into purpuric lesions
that are dusky red and have a diameter of 0.5-
This disorder
usually presents with red to purple bumps on the legs, often accompanied by
aching in the joints and fever. This condition follows an infection and usually
resolves without treatment. Skin lesions most commonly occur below the knee but
may also be seen on the thigh, buttocks, and rarely on the arms.
Henoch-Schonlein
purpura is more commonly seen in children than adults and often occurs after an
upper respiratory infection. It causes skin rashes that bleed into the skin
(petechiae and purpura). Bleeding may also occur from the gastrointestinal
tract and kidneys.
In women, gynecologic symptoms can include
painful menstruation.
Henoch-Schoenlein purpura can be accompanied
by neurologic manifestations,
particularly headaches. Ozkaya et al reported cerebral vasculitis in a child
with Henoch-Schoenlein purpura and familial Mediterranean fever.
In rare cases, Henoch-Schoenlein purpura can
be associated with seizures, paresis, or coma. Other manifestations include
altered mental status, apathy, hyperactivity, irritability, mood lability,
somnolence, seizures (partial, complex partial, generalized, status
epilepticus), and focal deficits (eg, aphasia, ataxia, chorea, cortical
blindness, hemiparesis, paraparesis, quadriparesis).
Polyradiculoneuropathies
(eg, brachial plexus neuropathy, Guillain-Barré syndrome) and
mononeuropathies (eg, facial nerve, femoral nerve, peroneal nerve, sciatic
nerve, ulnar nerve) may also occur.
The liver
and gallbladder can be involved in Henoch-Schoenlein purpura. Hepatomegaly,
hydrops of the gallbladder, and cholecystitis may ensue. These may contribute
to a patient's abdominal pain. Acute appendicitis has been noted in patients
with Henoch-Schoenlein purpura.
Skin involvement is usually purpura. Chan et
al noted a case of Henoch-Schoenlein purpura presented as painful bullae on
both legs.
Acute
hemorrhagic edema of infancy (AHEI) usually occurs in infants aged 4-24 months.
AHEI often occurs after drug ingestion or infection. The onset of AHEI is
dramatic, with acute palpable purpura, ecchymoses, and tender edema of the
limbs and face. Fever, if present, remains mild. Infants remain hemodynamically
stable. Dermatologic findings are notable for a cockade (medallionlike),
rosette-shaped pattern of macular-papular-hemorrhagic lesions on the face,
auricles, and extremities. The lesions usually appear in successive crops. The
cockades display variable stages of evolution at any given time.
Subcutaneous
edema is most common in infants. Urticaria, petechiae, and ear lobe necrosis
are additional rare skin manifestations of AHEI. Visceral involvement is rare.
Renal
pathology is the most important cause of morbidity and mortality in patients
with Henoch-Schoenlein purpura. Renal involvement may precede skin
manifestations (1-4% of patients) but is usually evident during the acute phase
of the disease. In most cases, the severity of nephritis is not related to the
extent of other Henoch-Schoenlein purpura manifestations. The
most serious complication of Henoch-Schoenlein purpura is renal involvement,
which occurs in 50% of older children but is serious in only approximately 10%
of patients. In 80% of patients, renal involvement becomes
apparent within the first 4 weeks of illness. Overall, 2-5% of patients
progress to end-stage renal failure (ESRF). In one series, acute
glomerular lesions, including mesangial hypercellularity, endocapillary
proliferation, necrosis, cellular crescents, and leukocyte infiltration, were
observed in 41%, 12%, 50%, 29%, and 32% of patients,
respectively. Only glomerular necrotizing lesions and cellular
crescents correlated with the renal survival rate and were associated with
clinically significant proteinuria and development of hypertension.
Granular IgA staining in the walls of
small dermal vessels in a patient with Henoch-Schönlein purpura.
|
|
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Hematuria, usually microscopic, can be
accompanied by mild-to-moderate proteinuria (< 2 g/d). Oliguria,
hypertension, and azotemia are rarely present. Nephrotic syndrome (urinary
protein excretion >40 mg/m2/h) can also occur. In most cases,
histologic examination of the kidneys reveals mesangial proliferation that can
be diffuse or focal and segmental. Resolution of the renal involvement is the
focus in these patients.
Patients
who present with hematuria and persistent proteinuria have an approximate 15%
risk of developing renal failure. The risk may increase to 50% in patients with
a nephrotic-nephritic syndrome.
Urinary complications include bladder-wall
hematoma, calcified ureter, hydronephrosis, and urethritis.
Hemoptysis
and hemarthroses can develop in patients who have bleeding abnormalities such
as coagulopathy, factor VIII deficiency, vitamin K deficiency, or
hypoprothrombinemia. They also probably include factor V Leiden, protein C
deficiency, and protein S deficiency, but this has not been documented.
Diagnosis
There is
no definitive test to diagnose Henoch-Schönlein purpura. The clinical
triad of purpura, abdominal pain, and arthritis should raise concern. Palpable
purpura in the absence of thrombocytopenia is most suggestive and is present in
all patients. Punch biopsy of the skin is useful to show
the characteristic leukocytoclastic vasculitis. Renal biopsy will demonstrate a
membranoproliferative glomerulonephritis similar to IgA nephropathy.
In 1990,
the
Diagnostic Criteria for Henoch-Schönlein Purpura
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|
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Presence of two or more
of the following: ·
Palpable
purpura without thrombocytopenia ·
Patient
20 years or younger at disease onset ·
Bowel
angina (diffuse abdominal pain or diagnosis of bowel ischemia) ·
Biopsy
showing granulocytes in the walls of small arterioles or venules |
|
International Consensus
Conference, 2006 |
|
Palpable purpura in the
presence of one or more of the following: ·
Diffuse
abdominal pain ·
Any
biopsy showing predominant immunoglobulin A deposition ·
Arthritis
(acute, any joint) or arthralgia ·
Renal
involvement (any hematuria or proteinuria) |
Because there are no
definitive serologic tests for Henoch-Schönlein purpura, the purpose of
laboratory evaluation is to identify complications or exclude other diseases .
Useful baseline studies include renal function tests (e.g., electrolytes, blood
urea nitrogen, creatinine, urinalysis), complete blood count with platelet
count, coagulation profile (e.g., prothrombin time, partial thromboplastin
time, fibrinogen, fibrin degradation products), and IgA levels. A normal
platelet count, leukocytosis, eosinophilia, azotemia, elevated serum IgA
levels, hematuria, proteinuria, and red blood cell casts are commonly seen. The
need for blood cultures, antistreptolysin-O titers, renal biopsy, and tests to
identify other infectious agents depends on the presence of clinical indicators
of specific infections or progressive renal disease.
Laboratory Studies
No
specific diagnostic laboratory test is available to assess for markers of
Henoch-Schoenlein purpura (HSP). Coppo et al reported that in patients in whom
severe proteinuria, hypertension, or crescents are present at onset, the risk
for Henoch-Schoenlein purpura progression is greater in adults and females and
appears linked with increasing mean proteinuria levels during follow-up, even
more so than in patients with decreased renal function at onset. Factor
XIII activity apparently correlates tightly with the severity of abdominal
manifestations, and, thus, measuring factor XIII activity aids in identifying
patients with severe GI manifestation who could benefit from substitution
therapy.
General
laboratory tests may reveal the following:
·
Antinuclear
antibody and rheumatoid factor are absent.
·
The
level of plasma coagulation factor XIII (F XIII) is reduced in about 50% of
patients.
·
Urinalysis
reveals hematuria. Proteinuria may also be found.
·
Antinuclear
antibody and rheumatoid factor are absent.
·
The
CBC count can show leukocytosis with eosinophilia and a left shift.
Thrombocytosis is present in 67% of patients.
·
Platelet
counts may be elevated. Low platelet levels suggest thrombocytopenic purpura.
The erythrocyte sedimentation rate (ESR) is variably elevated. Some reports
state that the ESR is mildly elevated in 75% of patients.
·
A
stool guaiac test may reveal occult blood. BUN and creatinine levels may be
elevated, indicating decreased renal function.
·
Plasma
D-dimer concentrations can be substantially increased.
·
Plasma
concentrations of TAT complex, PF-1, and PF-2 can be abnormal.
·
The
prothrombin time (PT) and activated partial thromboplastin time (aPTT) can be
reduced (eg, hypoprothrombinemia).
·
Serum
IgA levels are increased in about 50% of patients during the acute phase of
illness. Circulating IgA immune complexes may be present in some patients,
though data supporting the presence of classic antigen-antibody complexes have
been questioned.
·
Factor
VIII levels are decreased in some patients.
·
The
antistreptolysin O (ASO) titer is elevated in 30% of patients.
·
CH50
is decreased in 30% of patients.
·
C3
and C4 levels are occasionally low.
·
Immunocomplexes
of IgG and IgA can be increased.
Imaging Studies
Ultrasonography
Abdominal ultrasonography can be used if GI symptoms are present.
Diagnosis of Henoch-Schoenlein purpura using sonography and radionuclear
scanning in a child presenting with bilateral acute scrotum as the main symptom
of Henoch-Schoenlein purpura has been reported. In children with GI involvement
of Henoch-Schoenlein purpura, dedifferentiated wall thickening demonstrated by
ultrasound reveals a poor clinical prognosis. Bowel ultrasonographic findings
include thickening of the bowel wall, free fluid, and intussusception.
Hydrops
of the gallbladder is rarely seen.
Renal
involvement may result in no ultrasonographic features. If nephritis or
nephrotic syndrome occurs, renal enlargement with loss of corticomedullary differentiation
due to edema is observed.
Radiography
Plain radiography of the abdomen may help in diagnosing intestinal
obstruction, and a barium enema study may be used to confirm and treat
intussusception. Chest radiography may help in determining the presence and
extent of pulmonary hemorrhage. Testicular ultrasonography may help in
assessing the testes for hemorrhage or torsion.
Contrast-enhanced
radiography of the small intestine demonstrates thickened mucosal folds or
small barium flecks. Endoscopy may reveal multiple irregular ulcers, mucosal
redness, and petechiae in the duodenum. The second part of the duodenum is
sometimes predominantly affected. Ulcerating lesions accompanied by
hematomalike protrusions can be detected in patients with histopathologically
proven leukocytoclastic vasculitis.
MRI
Some suggest that MRI is useful to assess neurologic findings in
Henoch-Schoenlein purpura. Radiologic GI findings mainly include bowel ischemia
with thumbprinting and bowel-wall edema, which is sometimes visible on
abdominal radiographs.
If barium studies are
performed, typical findings of ischemic colitis may be found, including a
narrow colon with thickened mucosa and thumbprinting.
Some
believe that imaging studies are indicated only if the diagnosis is uncertain.
Histologic Findings
Henoch-Schoenlein purpura is a vasculitis that often involves the
kidneys.
Histopathologic
features of the skin lesions in infantile Henoch-Schoenlein purpura can range
from a typical leukocytoclastic vasculitis with or without fibrinoid necrosis
to the less specific findings of a lymphohistiocytic perivascular infiltrate
with extravasation of erythrocytes.
Direct immunofluorescence (DIF) testing is a useful adjunct to
histopathology; the yield of a positive test result is substantially higher
when the test is performed within 48 hours of presentation. Immunofluorescence
studies reveal perivascular IgA deposition in almost all patients; this finding
is rare in infantile Henoch-Schoenlein purpura, in which C3 and IgM are most commonly
found in the affected vessel walls.
The
histology of the kidney in Henoch-Schoenlein purpura widely varies. In some
cases, most glomeruli appear unaffected when assessed using light microscopy;
only a few show mesangial proliferation. In instances of moderate renal
involvement, focal and segmental intracapillary and extracapillary
proliferation may be present with adhesions and small crescents. Severe cases
are characterized by a diffuse proliferation with infiltration of neutrophils
and circumferential crescents in most of the glomeruli. Tubular atrophy and
interstitial infiltration with mononuclear cells may also be present.
Deposits of IgA in the mesangium and the walls of cutaneous capillaries
are detected in most patients. The IgA deposited in the mesangium is mainly of
the IgA1 subclass, although deposits of IgA2 are rarely noted. In addition to
IgA, the deposits in mesangium and cutaneous capillaries frequently contain C3,
IgG, and fibrin. The deposits of C3 are often accompanied by properdin, whereas
C1Q and C4 are usually not present. This observation suggests that the
complement components have been activated by means of the alternative pathway.
The
specific renal pathology of Henoch-Schoenlein purpura includes the following:
·
Diffuse hypercellularity
·
Focal and segmental proliferation
·
Mesangial proliferation
·
Minimal change to severe crescentic
glomerulonephritis
·
Segmental sclerosis fibrosis
·
Mononuclear cell infiltration
·
Mesangial, subendothelial, and subepithelial
deposits
·
Diffuse glomerular deposits of IgA, C3, fibrin, IgG,
properdin, and IgM
·
IgA deposits in the mesangium
Treatment
Because
Henoch-Schönlein purpura spontaneously resolves in 94 percent of children
and 89 percent of adults, supportive treatment is the primary intervention. Acetaminophen or nonsteroidal
anti-inflammatory drugs (NSAIDS) may be used to alleviate arthralgia, although
NSAIDS may aggravate gastrointestinal symptoms and should be avoided in
patients with known renal involvement. Relative rest and elevation of affected
extremities during the active phase of the illness may help prevent purpura.
Patients should be advised that they may experience recurrent purpura as they
increase their activity level.
Hospitalization may be required when adequate
outpatient monitoring is unavailable or if dehydration, hemorrhage, or pain
control require inpatient management. Nephrology referral is recommended with
significant renal involvement. In
patients with severe renal disease, renal biopsy is needed to provide a
definitive diagnosis and guide therapy.
Early steroid
treatment is most appropriate for patients with renal involvement or severe
extrarenal symptoms. It may also
help relieve scrotal swelling. Oral prednisone at 1 to 2 mg per kg daily for
two weeks has been used to treat moderate to severe abdominal and joint
symptoms, and to hasten the resolution of Henoch-Schönlein purpura. Although prednisone did not
prevent renal disease, it was useful in treating renal disease after it
started. Early aggressive
therapy is recommended for adults with severe renal involvement.
Treatment options include high-dose steroids with immunosuppressants,
high-dose intravenous immunoglobulin, plasmapheresis, and renal
transplant. A recent trial found that cyclophosphamide (Cytoxan) was
effective in patients with overt nephritis, although cyclosporine
(Sandimmune) was not helpful.
Treatment Principles for Henoch-Schönlein Purpura
|
Symptom severity |
Treatment |
|
Minimal |
Supportive care |
|
Mild (mild arthralgias or
abdominal pain) |
Acetaminophen or
nonsteroidal anti-inflammatory drug |
|
Moderate (significant
arthritis, abdominal pain, or early renal involvement) |
Corticosteroids* |
|
Consider subspecialty
consultation† |
|
|
Severe (progressive renal
disease, pulmonary hemorrhage) |
Corticosteroids* plus
adjunctive immunosuppressant (e.g., azathioprine [Imuran], cyclophosphamide
[Cytoxan], intravenous immunoglobulin) or plasmapheresis |
|
Arrange subspecialty
consultation† |
*— Recommended pediatric dosage is
prednisone 1 to 2 mg per kg daily for one to two weeks, followed by a taper.
†— Nephrology, gastroenterology,
surgery, rheumatology, or other subspecialty as determined by presenting
symptoms or organ systems involved.
Follow-up
Care and Prognosis
Henoch-Schönlein purpura is a
self-limited illness that demonstrates no clinical sequelae in most patients
without renal involvement. Most patients recover fully within four weeks.
Recurrences of Henoch-Schönlein purpura occur in up to one third of
patients within the first six months after onset and are more common in patients
with renal involvement.
Long-term prognosis depends on the
severity of renal involvement; end-stage renal disease occurs in 1 to 5 percent
of patients. One systematic
review revealed that the onset of renal disease in patients with
Henoch-Schönlein purpura developed within four weeks in 85 percent of
patients, six weeks in 91 percent of patients, and six months in 97 percent of
patients. Permanent renal impairment did not develop in patients with a normal
urinalysis, although it occurred in 19.5 percent of patients with nephritic or
nephrotic syndrome.
A blood pressure measurement and
urinalysis should be performed at the time Henoch-Schönlein purpura is
diagnosed and at each return physician office visit. Serum blood urea nitrogen and
creatinine determination are needed if hematuria or proteinuria are identified. If the initial urinalysis is normal,
or if there is isolated hematuria (without nephritic or nephrotic syndrome), a
monthly urinalysis should be performed for the first six months after the
diagnosis of Henoch-Schönlein purpura. This
will detect the first signs of renal involvement, and facilitate early
nephrology consultation and the initiation of steroids.
Hypersensitivity
Vasculitis (Leukocytoclastic Vasculitis)
Hypersensitivity
vasculitis (leukocytoclastic vasculitis, or LCV) is a histopathologic term
commonly used to denote a small-vessel vasculitis. Many possible causes exist
for this condition, but a cause is not found in as many as 50% of patients. Hypersensitivity vasculitis (leukocytoclastic
vasculitis) may be localized to the skin, or it may manifest in other
organs. The internal organs most commonly affected are the gastrointestinal
tract and the kidneys. Joints are also commonly affected. The prognosis is good
when no internal involvement is present. The disorder may be acute or chronic.
ETIOLOGY. As indicated by the terminology, the
etiology is usually a recognizable antigenic stimulus such as a drug, microbe,
toxin, or foreign or endogenous protein. From an etiologic standpoint the
hypersensitivity vasculitides segregate into two distinct groups, depending on
the source of the sensitizing antigen. In the classic original group, the
antigen is foreign to the host. In the second group the antigen is enclogenous.
For example, certain connective tissue diseases may manifest a typical
hypersensitivity small vessel vasculitis. These diseases are generally
characterized by circulating immune complexes in which one of the components is
an endogenous protein to which antibody is directed. This is true of patients
with systemic lupus erythematosus who develop immune complexes composed of
endogenous DNA and anti-DNA antibodies; in addition, patients with rheumatoid
arthritis may develop immune complexes of rheumatoid factor with antibody activity
against endogenous immunoglobulin. Thus, in most of the hypersensitivity
vasculitides, the identity of the etiologic agent which triggers the formation
of immune complexes is at least strongly suspected.
·
Between one third and one half of cutaneous vasculitis cases are
idiopathic; the remainder have a variety of causes.
·
Antibiotics are the most common drugs that can cause cutaneous
vasculitis, particularly beta-lactams. Nonsteroidal anti-inflammatory drugs and
diuretics also frequently cause vasculitis. However, almost all drugs are
potential causes.
·
Various infections may be associated with vasculitis. Upper respiratory
tract infections (particularly beta-hemolytic streptococcal infection) and
viral hepatitis, particularly hepatitis C, are most often implicated. HIV
infection may also be associated with some cases of cutaneous vasculitis.
Ascertaining whether a drug (eg, antibiotic) or an infection (eg, upper
respiratory infection) is responsible for the disease is impossible because the
occurrence of vasculitis postdates infection and the drug used to treat the
infection.
·
Foods or food additives may cause vasculitis.
·
Hepatitis C is a regularly recognized cause of vasculitis, probably
through the presence of cryoglobulins. However, of 1614 patients with hepatitis
C, vasculitis occurred in only 12 patients (9 with cryoglobulinemia, 3
without). Interestingly, cryoglobulins were present in roughly 40% of those
tested; many patients with cryoglobulins (98%) did not have vasculitis despite
an abnormal circulating paraprotein. Hepatitis B was implicated in some cases
of vasculitis in the past.
·
Collagen vascular diseases account for 10-15% of cases of vasculitis.
o
In particular, rheumatoid arthritis, Sjögren syndrome, and lupus
erythematosus may have an associated vasculitis.
o
The presence of vasculitis often denotes active disease and possibly a
poorer prognosis.
·
Inflammatory bowel disease, ulcerative colitis, or Crohn colitis may be
associated with cutaneous vasculitis.
·
Malignancy accounts for less than 1% of cases of cutaneous vasculitis.
o
Perhaps lymphoproliferative diseases are more common (particularly hairy
cell leukemia); however, any type of tumor at any site may possibly be related
to cutaneous vasculitis.
o
Effective tumor therapy in some patients has led to resolution of the
vasculitis.
·
Small-vessel cutaneous vasculitis may be seen uncommonly in patients with
a larger vessel vasculitis, such as Wegener granulomatosis, polyarteritis
nodosa, or Churg-Strauss syndrome.
INCIDENCE AND PREVALENCE. It is difficult to determine an accurate incidence for the
hypersensitivity group of vasculitides owing to the marked heterogeneity among
these diverse syndromes. However, the hypersensitivity group of vasculitides is
much more common than the polyarteritis group and other syndromes such as
Wegener's granulomatosis and Takayasu's arteritis. The disease can be seen at
any age and in both sexes; however, this varies considerably with the
particular subgroup in question.
PATHOLOGY AND PATHOGENESIS. The histopathologic hallmark of the hypersensitivity
vasculitides is a leukocytoclastic venulitis. The term leukocytoclasis refers
to nuclear debris derived from the neutrophils that have infiltrated in and
around the involved vessels. In skin biopsies, this type of involvement is most
common in the postcapillary venules just beneath the epidermis. When biopsies
are obtained in the acute phase of active disease, the typical pattern of
neutrophil infiltration is readily observed. In the subacute or chronic stages,
biopsies often reveal mononuclear cell infiltration. In the second and smaller
category of hypersensitivity vasculitis, arterioles and capillaries are
predominantly involved. In the typical case of hypersensitivity vasculitis with
a predominance of cutaneous involvement, the lesions are usually found in the
lower extremities or in the dependent areas such as the sacrum in supine
patients. This is most likely due to the increase in hydrostatic pressure
within the postcapillary venules in these areas.
Although
immune complex deposition is widely considered to be the pathogenic mechanism
of this group of vasculitis, not every case of hypersensitivity vasculitis has
had immune complexes demonstrated, even when carefully sought, as mentioned
above.
In the past, circulating immune
complexes were believed to cause hypersensitivity vasculitis (leukocytoclastic
vasculitis). Although immune complexes are involved in the
pathogenesis of hypersensitivity vasculitis (leukocytoclastic vasculitis),
other autoantibodies cause disease manifestations, such as antineutrophil
cytoplasmic antibody (ANCA), other inflammatory mediators, and local factors
that involve the endothelial cells and other adhesion molecules. The
exact mechanisms remain to be elucidated. The incidence of hypersensitivity
vasculitis (leukocytoclastic vasculitis) is unknown, but the condition is
presumed to be rare.
Hypersensitivity vasculitis
reportedly has an incidence of 10-30 cases per million people per year.
Henoch-Schönlein purpura reportedly has an incidence of 14 cases per
million people per year. Hypersensitivity
vasculitis (leukocytoclastic vasculitis) is reported most often in the white
population. Hypersensitivity vasculitis
(leukocytoclastic vasculitis) affects men and women in approximately equal
proportions. Some of the studies from Spain suggest that hypersensitivity
vasculitis (leukocytoclastic vasculitis) is slightly more common in men than in
women. Hypersensitivity vasculitis
(leukocytoclastic vasculitis) may occur at any age. In children,
hypersensitivity vasculitis (leukocytoclastic vasculitis) may be called
Henoch-Schönlein purpura. This condition may also occur in adults. Another
form of vasculitis that is reported in infancy is acute hemorrhagic edema.
Ñlinical
History
• Patients with vasculitis of their skin
may report itching, a burning sensation, or pain, or they may have asymptomatic
lesions.
·
Vasculitis of the skin may occur in the absence of any systemic disease.
·
Vasculitis may manifest as an eruption only, or it may occur in
conjunction with collagen vascular disorders, paraproteinemia, ingestants
(drugs or foods), infections, or malignancy (rare).
·
Elicit information about possible systemic manifestations from patients.
Inquire about the presence or the absence of fever, arthralgia, arthritis,
myalgia, abdominal pain, diarrhea, hematochezia, cough, hemoptysis, sinusitis,
paresthesia, weakness, and hematuria.
·
Obtain information about symptoms of an associated disorder. Determine
the patient's history of intravenous drug use, hepatitis, transfusion, and
travel, along with symptoms or a history of inflammatory bowel disease and
collagen-vascular disorder, particularly rheumatoid arthritis, lupus
erythematosus, or Sjögren syndrome.
Palpable
purpura is the most common manifestation of cutaneous vasculitis, but other
manifestations may occur.
·
Palpable purpura is the most frequent presentation of small-vessel
vasculitis.
o
Lesions are usually round and 1-
o
Lesions may coalesce to form plaques; they may ulcerate in some
instances.
o
Retiform lesions were associated with immunoglobulin A (IgA)–related
immune complex disease in one study; however, this result has not been
validated in subsequent studies.
o
Palpable purpura is most frequently observed on the legs, but any surface
can be involved. Purpuric lesions are sometimes barely palpable.
http://drugline.org/img/term/vasculitis-allergic-15822_1.jpg
http://drugline.org/img/term/vasculitis-allergic-15822_2.jpg
·
Urticarial lesions may occur in some patients; rarely, this type of
lesion can predate purpuric lesions.
o
Urticarial lesions are of a different character than routine urticaria,
tending to be of longer duration (often >24 h) and tending to resolve with
some residual pigmentation or ecchymosis. Patients complain of a burning
sensation rather than itching.
o
To determine the duration of individual lesions, encircle several lesions
and ask the patient to observe them periodically and note when they resolve or
when they change shape and when a lesion is outside the encircled area.
·
Patients with hypocomplementemic urticarial vasculitis may develop
chronic obstructive pulmonary disease; carefully examine the heart and the
lungs
·
Livedo reticularis is a rare manifestation of small-vessel vasculitis. It
is more frequent in patients with occlusive or inflammatory disease of
medium-sized vessels.
·
Nodular lesions may occur in some patients with small-vessel vasculitis.
·
Ulceration is more common in vasculitis that affects larger vessels, but
it may complicate intense purpura.
·
Perform a careful physical examination in patients with vasculitis,
including specific observation of cardiopulmonary, musculoskeletal, and
gastrointestinal systems.
|
|
|
Histopathologic features of
leukocytoclastic vasculitis. |
Erythema elevatum diutinum, a rare cutaneous vasculitis.
·
Evaluation of patients with hypersensitivity vasculitis (leukocytoclastic
vasculitis) serves 2 purposes: to determine the presence of systemic disease
and to identify an associated disorder, which aids in predicting the patient's
prognosis.
·
No established routine exists, but testing for all adult patients
includes a complete blood count, an erythrocyte sedimentation rate, a
urinalysis, and a blood chemistry panel.
·
Obtain stool guaiac or Hematest for patients with bowel symptoms even
though these tests are not particularly reliable.
·
Obtain serologic studies (eg, antinuclear antibody, ANCA [ie, circulating
ANCA, perinuclear ANCA, atypical ANCA], rheumatoid factor) for patients without
an obvious disease cause. In children and perhaps in some adults, serologic
testing for a possible streptococcal infection should be considered
(Streptozyme or ASO titer).
·
Complement levels, including total hemolytic complement (CH100 or CH50),
C3 levels, and C4 levels, may be obtained for patients suspected of having
lupus erythematosus or patients who have urticarial vasculitis.
·
Include serum protein electrophoresis, cryoglobulins, and hepatitis C
antibody in tests for paraproteins for patients without otherwise identified
disease.
o
Hepatitis B was associated with vasculitis in the past; however, it
appears that the association may have occurred by virtue of co-infection with
hepatitis C (previously termed non-A, non-B).
o
The measurement of hepatitis B surface antigen may not be required in all
cases.
o
Cryoglobulins are often not obtained properly; a positive rheumatoid
factor should suggest the presence of cryoglobulins.
·
Perform HIV testing for patients at high risk for infection and possibly
for those with otherwise unidentifiable cause of disease.
·
Consider obtaining direct immunofluorescence microscopy for selected
patients. The presence of IgA occurs in Henoch-Schönlein purpura.
·
Chest radiography is part of the routine evaluation.
·
Consider performing visceral angiography for patients with a severe
vasculitic syndrome.
·
Perform cardiac ultrasonography and blood cultures for patients with
fever and/or a heart murmur.
·
Obtain pulmonary function tests for patients with hypocomplementemic
urticarial vasculitis.
·
Perform a skin biopsy of a relatively fresh lesion in most, if not all,
adult patients. For humanitarian reasons, biopsies are often not performed in
children with suspected vasculitis.
·
Consider performing a biopsy of muscle or a biopsy of visceral organs in
patients with severe vasculitic syndromes; however, most patients with
leukocytoclastic vasculitis of the skin do not require such tests.
·
Obtaining a bone marrow sample may be useful if the peripheral smear is
abnormal.
A skin biopsy sample reveals the presence of vascular and
perivascular infiltration of polymorphonuclear leukocytes with formation of
nuclear dust (leukocytoclasis), extravasation of erythrocytes, and fibrinoid
necrosis of the vessel walls. This process is dynamic; a biopsy sample of a
lesion too early or too late in its evolution may not reveal these findings.
The picture of leukocytoclastic
vasculitis is a pattern that can occur in any vasculitic syndrome but may also
occur in nonvasculitic diseases (eg, neutrophilic dermatoses), at the base of a
biopsy sample of a leg ulceration, or in some insect bite reactions. Careful
clinical-pathologic correlation is necessary.
Therapy of
the hypersensitivity group of vasculitides has in general been unsatisfactory.
Since most cases resolve spontaneously, the lack of response to therapeutic
regimens is of less importance. However, in those patients who go on to develop
persistent cutaneous disease or serious organ system involvement, several
regimens have been tried with variable results. In cases in which a recognized
antigenic stimulus is present, the first order of therapy is to remove the
antigen; e.g., to remove sensitizing drugs or responsible organisms by
appropriate antibiotic therapy when possible. In situations in which disease
appears to be self-limited, no specific therapy is indicated. However, when
disease persists or results in organ system dysfunction, a glucocorticosteroid
is the drug of choice. Prednisone is usually administered in doses of 1 mg per
kilogram per day with rapid tapering when possible, in some instances directly
to discontinuation or initially to an alternate-day regimen followed by
ultimate discontinuation. In cases that prove refractory to corticosteroid
therapy, cytotoxic agents such as cyclophosphamide have been used.
Once a
diagnosis of hypersensitivity vasculitis (leukocytoclastic vasculitis) is
established and the patient is fully evaluated, specific or nonspecific
management options may be used.
·
Elevation of the legs or compression stockings may be useful because the
disease often affects dependent areas.
·
Treat the cause in patients with an identifiable cause. Removal of a drug
thought to be causing the vasculitis may result in rapid clearing of the
process in up to 2 weeks.
·
Treat chronic disease that primarily involves the skin with nontoxic
modalities whenever possible; avoid using systemic corticosteroids and/or
immunosuppressive agents. Colchicine or dapsone may be administered
for patients with disease of the skin with or without joint manifestations.
·
Patients with urticarial lesions may be treated with antihistamines (both
soporific ones and less sedating agents). Sometimes, a combination of these
agents is needed to control disease manifestations. Some patients have responded
to nonsteroidal anti-inflammatory agents.
·
Patients with severe visceral involvement may require high doses of
corticosteroids (1-2 mg/kg/d) with or without an immunosuppressive agent (eg,
cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil).
·
Rituximab has been reported in various subsets of vasculitis, including
several patients with chronic cutaneous small-vessel vasculitis.
·
Consider a restrictive diet for patients with chronic cutaneous
vasculitis without other identifiable causes.
·
Surgical Care
·
Surgical care is rarely needed for patients with hypersensitivity
vasculitis (leukocytoclastic vasculitis). Surgical care may be appropriate if a
tumor is identified as a cause of the process. Surgical care also may be
appropriate if recalcitrant ulceration occurs after control of active disease.
References
A
-
1.
Davidson’s Principles and practice of
medicine (21st revised ed.) / by Colledge N.R.,
Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. –
1376 p.
2.
3.
The Merck Manual of Diagnosis and
Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others.
– published by Merck Research Laboratories, 2011.
4.
Web -sites:
http://emedicine.medscape.com/
http://meded.ucsd.edu/clinicalmed/introduction.htm
B
- Optional:
1.
Clinical Rheumatology (The
Clinical Medicine Series) 12 edition/ Pacific Primary Care Software
PC/ M.D., C. G. Weber.-2011.- 526 p.
2.
Kelley's Textbook of
Rheumatology, 9th Revised edition / Firestein, Gary S.; Budd, Ralph
C.; Gabriel, Sherine E.; O'Dell, James R.; McInnes, Iain
B.-2012.- 2292 p.
3.
Vasculitis in Clinical
Practice,1st Edition/ Richard A. Watts; ); David G. I.
Scott/ Springer.- 2010.- 215 p.