Systemic group revised and validated the American College of

Systemic lupus
erythematosus (SLE) is a subtype of lupus erythematosus, a complex chronic
autoimmune inflammatory disorder, acting multi-systemically, with widely varying, and unpredictable clinical features. It is present in both genders and all age ranges but
predominantly affecting Black and Asian women of childbearing age (Lu
et al., 2009; et al., 1995). It can be
characterised by the
production of autoantibodies, complement consumption, and the presence of
circulating immune complexes, leading to inflammation and tissue damage (Crowson and Magro, 2001).

 

            In
2012 the Systemic Lupus International Collaborating Clinics (SLICC) group
revised and validated the American College of Rheumatology SLE classification
criteria (Petri et al., 2012),
and derived a list of 11 clinical and 6 immunological criteria for the signs and
symptoms of SLE, see below with descriptions of the salient points.

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Malar
rash, the classic “butterfly” rash across the face presenting as red
or purplish and mildly scaly. In some sufferers, this rash can be exacerbated
by UV exposure.Discoid
rash, a more severe rash and skin inflammation leading to scaring of the face,
ears and scalp. In some sufferers, this rash can be exacerbated by UV exposure.Oral
ulcers.Hair
loss.Joint
pain (Synovitis), usually in the small bones of the hands and
wrists, usually with swelling or effusion, this is specifically a non-erosive
arthritis. Unlike rheumatoid arthritis, the joint is not usually severely
damaged. Nearly 90% of sufferers experience joint and/or muscle pain.Pleurisy
leading to shortness of breath and pain upon deep inhalation.Pericarditis,
myocarditis, and/or endocarditis.Kidney
inflammation, causing proteinuria, swelling of lower limbs, and elevated blood
pressure.Neurological
conditions including seizures, psychosis, acute confusional state, and nerve
inflammation.Anaemia
is especially common in younger sufferers, affecting red blood cells, white
blood cells, lymphocytes, and/or platelets.Antinuclear antibody presence.Anti-double stranded DNA antibody presence.Anti-Sm
antibody presence (Smith protein antigen antibodies.)Antiphospholipid
antibody presence (e.g. Lupus anticoagulant)Low
complement results.Positive
Direct Coombs’ test. However, in addition to these criteria patients also present with
not easily definable symptoms;Muscle
pain.Dry or
puffy eyes and photosensitivity.Extreme
fatigue.Raynaud’s
phenomenon, constriction of the arteries causing reduced perfusion, white or
blue of fingers with exposure to cold.  Given
the range of symptoms, the complexity and mimicry of other diseases, the
diagnostic pathway for SLE is complex and multidisciplinary.  As SLE can flare
and subside, there is a need for multiple observation periods and diagnostic
tests. The current internationally accepted method for diagnosis is that
on two separate presentations a patient is diagnosed with at least 4 of the 11
criteria developed by the American College of
Rheumatology, as described in Table 1 below taken from (Tan et al., 1982). The classic serological test is detection of
immunoglobulins deposits and complement proteins at the dermo-epidermal
junction by means of a direct immunofluorescence staining. Reich et al
emphasise that this test “should always be interpreted in conjunction with
clinical findings and other serological and immunopathological parameters” (Reich et al., 2011), typically
this would involve detection of Anti-dsDNA antibodies which are highly specific
to SLE patients (present in 70% of suffers but on 0.5% in non-SLE).  

Table
1: The 1982 revised criteria for
classification of systemic lupus erythematosus (Tan et al., 1982).

 

 

The effects of SLE in the Cardiovascular system will be discussed
in more detail as the elevated risk of cardiovascular disease (CVD) has been
recognised since 1976 when Urowitz and Gladman
reported the bimodal mortality pattern of SLE (Urowitz et al., 1976), with early mortality coinciding with infection and active SLE,
while late mortality coincides with CVD and inactive SLE. The elevated risk of
CVD in SLE patients cannot be explained by “traditional” risk factors such as
age, hypertension, or diabetes. Instead SLE instigated factors have been
described as potential contributive factors (Vlachoyiannopoulos, 2003). As well as inflammatory effects on
the three layers of the heart, it is also know that atherosclerosis is more
common and progresses more aggressively in SLE sufferers (Hahn, 2003; Frieri and Stampfl,
2016), and due to Lupus Nephritis hypertension
occurs in a significant number (50%+) of SLE patients.

Inflammation of the fibrous sac surrounding the heart or
Pericarditis causes sudden sharp chest pains, typically worse when lying or
taking a deep breath than sitting. Myocarditis is an inflammation of the heart
muscle expressed as shortness of breath, chest pain and irregular heartbeat.
Leading to congestive heart failure when the heart is no longer able to
maintain a sufficient blood flow. The inflammation of the hearts internal
lining (Endocarditis) produces vegetation’s on the surface of the hearts
valves. These lesions become prime sites for infection, the risk of
embolization and stroke due to part of the vegetation breaking off and
travelling to the brain.

Accelerated atherosclerosis is the major cause of late mortality in
SLE patients (Stojan and Petri, 2013), it is thought this occurs due to
the autoimmune nature of SLE interfering with vascular repair by promoting
anti-angiogenesis, repression of vascular endothelial growth factor and promoting
a pro-inflammatory cytokine IFN-?. This influences foam cell formation,
specific immune responses and plaque development, all classically associated
with atherosclerosis (McLaren and Ramji, 2009).

The worsening renal function in SLE patients is seen as reduced
glomerular filtration rate, associated with increased CVD rates (Frieri and Stampfl, 2016; Doria,
2003; Selzer et al., 2004). As the filtration rate drops
sodium balance, and body fluid levels are maintained by a reciprocal increase
in arterial pressure. Chronic hypertension is directly linked to increased
arterial damage, leading to aneurysms and increased rate of fatty deposition,
vessel narrowing, left ventricular hypertrophy (leading to higher risk of heart
failure and sudden cardiac death), coronary artery disease, transient ischemic
attacks, strokes, and in a circular manner greater kidney damage.

 

Given the complexity of SLE, it is not surprising that
its instigation is thought to be equally as multifarious. Strong evidence for a
genetic component is the >66% inheritance, and >35% shared susceptibility
in monozygotic twins (Moser
et al., 2009). Current evidence suggests
multi-gene genetic susceptibility triggered by environmental factors, and
disturbances in the immune system (Lisnevskaia et al., 2014; Wahren-Herlenius and Dörner, 2013).

Genome wide studies have found 28+ SLE specific loci (Guerra et al., 2012); however, the strongest association is in the MHC
locus. This locus is a known location for signals from both antigen-presenting
and non-antigen-presenting genes (Wahren-Herlenius
and Dörner, 2013). Of these, the HLA-DR3 is firmly
linked to the production of antibodies against DNA (Taylor
et al., 2011) a
classic symptom of SLE. However this susceptibility must then be triggered by a
range of environmental factors including; UV radiation, tobacco smoke,
infection, vaccination (highly rare), vitamin D deficiency (making avoiding UV
radiation problematic), oestrogen (hence the gender disparity), pharmaceutical
agents, pesticides, organic solvents, phthalates (plasticising agents) (Lisnevskaia
et al., 2014).

 

Currently
there is no cure for SLE, however >90% survive more than 10 years with
ever-increasing symptom free life expectancy (Kuhn et
al., 2015). Treatment for acute inflammation, pain, skin rash, and
fatigue are covered by common medications such as NSAIDs (Lander et al., 2002), and steroid creams and
injections. However, for more chronic use, there are off-label anti-malarials (Ruiz-Irastorza et al., 2008), which help combat
fatigue, cholesterol and kidney disease as well as allowing reduced steroid
usage. Anti-hypertensive drugs are vital in their role to reduce the
significant risks to the cardiovascular system (Tselios
et al., 2014), while specific vasodilators can be used for those
patients who have the Raynaud’s phenomenon aspects of SLE.

The
most exciting interventions however do not specifically target the symptoms,
but rather the underlying cause, specifically acting against the autoimmune
aspect of SLE. Disease-modifying anti-rheumatic drugs, act in an
immuno-suppressant manner but also serve to control high blood pressure and
prevent kidney problems. A new form of treatment if targeted biological therapy
with the drugs rituximab (Cobo-Ibáñez et al., 2014) or
belimumab (Ginzler et al., 2013), which act
against B-lymphocytes and in so doing reduces the production of antibodies,
both these later two groups acting as close to the root cause as is currently
possible.