TREAT SYSTEMIC LUPUS ERYTHEMATOUS
Determining the appropriate therapeutic regimen requires an accurate
assessment of:
- Disease activity: manifestations of the underlying inflammatory
process at a point in time in terms of magnitude and intensity à
three patterns of disease: Intermittent disease flares / Chronically
active disease in terms of organ involvement / quiescent disease
- Disease severity: type and level of organ dysfunction and its
consequences, often described as mild, moderate, and severe
- patient's response to previous and ongoing therapeutic
interventions.
In clinical practice, disease activity and severity are assessed using a
combination of clinical history, physical examination, laboratory and
serologic studies as well as organ-specific tests:
- Clinical evaluation —
o All organ systems must be reviewed and examined
o Ask about any potential triggers such as sun exposure,
infection, or discontinuation of therapy.
- Laboratory evaluation — help assess disease activity and
monitor organ-specific complications (such as renal or
hematological). There is no single marker of disease activity, we
typically check:
o CBC with differential: Leukopenia, anemia and
thrombocytopenia may reflect active disease. Cytopenias
may also result from drug toxicities.
o ESR and CRP: Increases are commonly observed in patients
with SLE, and therefore may not be as reliable for detecting
disease. Nonetheless, an elevated ESR can be associated with
increased disease activity and accrued damage. An elevated
CRP should raise the suspicion for infection in a patient with
SLE.
o Urinalysis with examination of urinary sediment –
Proteinuria or cellular casts and hematuria may be due to
lupus involving the kidney.
o Spot urine protein-to-creatinine ratio – Quantification of
proteinuria helps assess the severity of glomerular disease
o Serum creatinine and eGFR – Elevations in creatinine may
reflect lupus nephritis.
o Anti-dsDNA – Titers often fluctuate with disease activity,
particularly in patients with active glomerulonephritis
o C3 and C4 – Low C3 and C4 and/or elevated C3 and C4
activation products often indicate active lupus, particularly
lupus nephritis.
- Additional studies — Monitoring for specific SLE-related organ
involvement typically requires additional studies such as ECG,
lung function tests, x-rays, CT scans, and renal or other organ (eg,
skin) biopsies.
- Monitoring frequency — depending on disease activity (eg every
one to two weeks in active lupus nephritis and every 3 to 4 months
in quiescent SLE)
- Flares:
o Definition: No consensus on what constitutes a disease flare,
but most definitions have incorporated a combination of
serologic measures and disease activity indices. A moderate
or severe flare refers to a measurable increase in disease
activity that is clinically meaningful enough to result in a
change in therapy. Exemples:
Symptoms Laborato Treatment
and signs ry
evaluatio
n
Mild
new onset mild
no treatment or addition
SLE
low-grade leukopen of hydroxychloroquine or the
flare
fevers, a
ia
equivalent of prednisone 7.5
malar rash,
mg per day or less.
and
arthralgias
,
increasingl
y fatigued
Modera pleuritic
te SLE chest pain
flare
and a
swelling
of the
wrists
Severe
SLE
flare
elevated
acute
phase
reactants
, rightsided
pleural
effusion
new onset low C3,
renal
C4,
insufficien elevated
cy and
dsDNA
significant antibodie
proteinuria s, and
due to
elevated
lupus
acute
nephritis
phase
reactants
short course of prednisone
high doses of glucocorticoids
(eg, 1 to 2 mg/kg/day
of prednisone or equivalent or
intermittent intravenous
"pulses"
of methylprednisolone),
additional immunosuppressive
therapy
(eg, cyclophosphamide, azathio
prine,
or mycophenolate mofetil),
and/or hospitalization.
o Predictors:
§ Of an SLE flare (particularly lupus nephritis) are the
onset of an increased serum titer of anti-dsDNA
antibodies and a fall in complement levels (especially
CH50, C3, and C4). Persistently low serum levels of
complement C1q are also associated with activity of
lupus nephritis
§ Other clinical features that are associated with an
increased risk of SLE flare include diagnosis of SLE
before age 25, patients who have renal, vasculitic, or
neurologic involvement.
NON PHARMACOLOGIC AND PREVENTIVE
INTERVENTIONS
a- Sun protection — and avoid exposure to direct or reflected sunlight
use sunscreens and avoid medications that can cause photosensitivity
(doxycycline, piroxicam, tolbutamide, furosemide, chlorthiazide,
hydrochlorothiazide, chlorpromazine, promethazine, amiodarone…)
b- Diet and nutrition — balanced diet consisting of carbohydrates,
proteins, and fats. (increase caloric intake when active inflammatory
disease and fever, vitamin D because of low serum levels of 25hydroxyvitamin D due to avoidance of sun exposure and/or use of
sunscreen products)
c- Exercise — Inactivity produced by acute illness causes a rapid loss
of muscle mass, bone demineralization, and loss of stamina resulting
in a sense of fatigue.
d- Smoking cessation — smoking has been associated with more
active disease and diminishes the efficacy of hydroxychloroquine
e- Immunizations — appropriate immunizations prior to
immunosuppressive therapies (Influenza, pneumococcal, HPV,
hepatitis B vaccines are safe). Live attenuated vaccines (eg, measles,
mumps, rubella, polio, varicella, zoster, and vaccinia [smallpox]) can
lead to complications in patients on immunosuppressive therapy.
f- Treating comorbid conditions — Accelerated atherosclerosis,
pulmonary hypertension, and antiphospholipid syndrome, as well as
osteopenia or osteoporosis can be screened and treated:
g- Issues with specific medications and therapies —
a- Sulfonamide-containing antimicrobials have been associated
with SLE allergies and exacerbations and should therefore be
avoided, if possible.
b- By contrast, medications that cause drug-induced lupus, such
as procainamide and hydralazine, do not cause exacerbations of
idiopathic SLE. Avoid the use of minocycline in patients with
established (idiopathic) SLE.
h- Pregnancy and contraception — Women with SLE should be
counseled not to become pregnant until the disease has been
quiescent for at least six months
PHARMACOLOGIC THERAPIES:
I-
Treatment of constitutional symptoms:
a- Hydroxychloroquine:
Risk factors for retinopathy: duration of treatment, dose, CKD, preexisting macular retinal disease
b- Glucocorticosteroids:
- longterm aim should
be to minimise daily
dose to ≤7.5 mg/day
prednisone
equivalent or to discontinue them
- two approaches can be considered: (1) use of pulses of IV
methylprednisolone (MP) of various doses (depending on severity
and body weight), which may allow for a lower starting dose and
faster tapering of PO GC, and (2) early initiation of IS agents, to
facilitate tapering and eventual discontinuation of oral GC.
- High-dose intravenous MP (usually 250–1000 mg/day for 3 days) is
often used in acute, organ-threatening disease (eg, renal,
neuropsychiatric) after excluding infections.
c- Immunosuppressive therapy:
- Methotrexate (MTX) and azathioprine (AZA) à relatively safe
profile.
- Published evidence is generally stronger for MTX than AZA, yet the
latter is compatible with pregnancy contemplation.
- Mycophenolate mofetil (MMF) is a potent immunosuppressant with
efficacy in renal and non-renal lupus (although not in
neuropsychiatric disease). It is teratogenic potential (needs to be
discontinued at least 6 weeks before conceiving),
- Cyclophosphamide (CYC) à
o in organ-threatening disease (especially renal, cardiopulmonary
or neuropsychiatric) and only as rescue therapy in refractory
non-major organ manifestations
o Gonadotoxic effects so use with caution in women and men of
fertile age.55–57 à Concomitant use of GnRH analogues
attenuates the depletion of ovarian reserve in premenopausal
patients with SLE. Information about the possibility of ovarian
cryopreservation should be offered ahead of treatment.
o Risk of malignancy and infections should also be considered
d- Biological agents:
-
Belimumab should be
considered in:
o extrarenal disease
with inadequate control to first-line treatments (typically
including combination of HCQ and prednisone with or without
IS agents), and inability to taper GC daily dose to acceptable
levels (ie, maximum 7.5 mg/day).
o More likely to respond are patients with high disease activity,
prednisone dose >7.5 mg/day and serological activity (low
C3/C4, high antidsDNA titres), with cutaneous, musculoskeletal
and serological manifestations.
- RTX is currently only used off-label, in:
o patients with severe renal or extrarenal (mainly haematological
and neuropsychiatric) disease refractory to other IS agents
and/or belimumab, or in patients with contraindications to these
drugs.
o More than one IS drug need to have failed prior to RTX
administration, except perhaps for cases of severe autoimmune
thrombocytopaenia and haemolytic anaemia, where RTX has
demonstrated efficacy both in lupus and in patients with (ITP).
o In LN, RTX is typically considered following failure of firstline therapies (CYC, MMF) or in relapsing disease.
II-
Treatment for specific SLE manifestations — There is
limited evidenced-based literature for managing organ-specific
manifestations outside of the kidney and skin manifestations.
- Fatigue: exclude other causes (depression, deconditioning, disordered
sleep, fibromyalgia, and iron-deficiency anemia) à then, low-dose
glucocorticoids and hydroxychloroquine
- Fever: after excluding an underlying infection
àNSAIDs, acetaminophen, and/or low to moderate doses of
glucocorticoids. Fever that does not respond to such therapy further
raises the suspicion of an infectious and/or drug-related etiology
- Specific organ system involvement —
a- Skin disease
- Effective
protection from
ultraviolet exposure with broad-spectrum sunscreens andsmoking
cessation are strongly recommended.
- A sizeable proportion (almost 40%) of patients will not respond to
first-line treatment à MTX can be added. Other agents include
retinoids, dapsone and MMF.
- Belimumab and RTX have also shown efficacy in mucocutaneous
manifestations of SLE; RTX may be less efficacious in chronic forms
of skin lupus.
- Thalidomide is effective in various subtypes of cutaneous disease.
Due to its strict contraindication in pregnancy, the risk for irreversible
polyneuropathy, and the frequent relapses on drug discontinuation, it
should be considered only as a ‘rescue’ therapy
b- Neuropsychiatric disease (NPSLE)
- Patients with SLE with cerebrovascular disease should be managed
like the general population in the acute phase
- in addition to controlling extra-CNS lupus activity, IS therapy may be
considered in the absence of aPL antibodies and other atherosclerotic
risk factors or in recurrent cerebrovascular events.
- Targeted symptomatic therapy (eg, antipsychotics for psychosis,
anxiolytics for anxiety disorder and so on).
c- Haematological disease
- Significant lupus
thrombocytopaenia (plt
< 30 000/mm3) :
o First-line treatment
is moderate/high doses of GC in combination with IS agent
(AZA, MMF or cyclosporine; the latter having the least
potential for myelotoxicity) to facilitate GC-sparing. Initial
therapy with pulses of intravenous MP (1–3 days) is
encouraged.
o IVIG in the acute phase, in cases of inadequate response to
high-dose GC or to avoid GC-related infectious complications.
o Treatment is typically lengthy and often characterised by
relapses during GC tapering.
o If no response to GC (ie, failure to reach a platelet count >50
000) or relapses, RTX should be considered. CYC may also be
considered in such cases.
o Thrombopoietin agonists or splenectomy reserved as last
options.
- Autoimmune haemolytic anaemia (AIHA) is less common than
thrombocytopenia in SLE; its treatment follows the same principles
regarding use of GC, IS drugs and RTX.
- Autoimmune leucopaenia is common in SLE but rarely needs
treatment; careful work-up is recommended to exclude other causes
of leucopaenia (especially drug-induced).
d- Renal disease
- Patients at high risk of developing renal involvement (males, juvenile
lupus onset, serologically active including positivity for anti-C1q
antibodies) à vigilant monitoring (eg, at least every 3 months) to
detect early signs of kidney disease.
- Diagnosis should be secured with a kidney biopsy
- Treatment of LN includes:
o initial induction phase, followed by a more prolonged
maintenance phase.
o MMF and CYC are the IS agents of choice for induction
treatment;
§ low-dose CYC is preferred over high dose (comparable
efficacy and lower risk of gonadotoxicity)
§ Use MMF or high-dose CYC in severe forms of LN
associated with increased risk of progression into endstage renal disease
o An early significant drop in UPr (to ≤1 g/day at 6 months or
≤0.8 g/day at 12 months) is a predictor of favourable long-term
renal outcome.
o MMF or AZA may be used as maintenance therapy, with the
former associated with fewer relapses; the choice depends on
the agent used for induction phase and on patient characteristics,
including age, race and wish for pregnancy.
o In refractory or relapsing disease, RTX may be considered.
o CNIs may be considered as second-line agents for induction or
maintenance therapy mainly in membranous LN,
podocytopathy, or in proliferative disease with refractory
nephrotic syndrome, despite standard-of-care within 3–6
months; they may be used alone or in combination with MMF.
e- Comorbidities:
- High risk aPL profile (ie, triple aPL positivity, lupus anticoagulant or
high titres of anticardiolipin antibodies)
- in patients with SLE-APS, use of novel oral anticoagulants for
secondary prevention should be avoided