SLE What's Going On

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SLE Whats going on

Hazem Suhail Ayesh
Pharmacological agents
Belimumab
Rituximab EXPLORER and LUNAR
Ocrelizumab Next generation Rituximab, BELONG
Epratuzumab anti- CD22
Tocilizumab promising
Abetimus Tolerance of B Cells, Molecular product
Atacicept BAFF, APRIL
Rigeromid Spliceosomal peptide
Abatacept RA or SLE
Infliximab Serious Side effects
Rituximab
Rituximab, a chimeric antibody targeting
CD20-positive cells, was first used by Tullus in
2000 in a girl with class V lupus nephritis and
therapy-resistant nephrotic syndrome. The
therapeutic response was remarkable and her
proteinuria improved so much that her serum
albumin normalized.
EXPLORER, which included 237 patients with
moderate to severe extra-renal lupus did not
find any difference between rituximab and
placebo.
Efficacy and safety of rituximab in the

treatment of non-renal systemic lupus
erythematosus: A systematic review.
Conclusion: Rituximab has been shown to be
safe and effective in the treatment of nonrenal SLE, especially in terms of disease
activity, immunologic parameters and
steroid-sparing effect. However, it can only
be recommended for organ-specific
manifestations such as arthritis and
thrombocytopaenia. High-quality studies are
needed in order to consider the long-term
effects of re-treatment on different organspecific manifestations
Rituximab in the Treatment of Shrinking

Lung Syndrome in Systemic Lupus
Erythematosus
Shrinking lung syndrome (SLS) is a rare
manifestation of systemic lupus
erythematosus. We report the case of a
patient with non-responding SLS (neither to
glucocorticoid or immunosupresors), who
showed remarkable improvement after the
onset of treatment with rituximab. Although
there is a little evidence, treatment with
rituximab could be proposed in SLS when
classical treatment fails.
Belimumab
Belimumab is a fully humanized
monoclonal antibody that binds to
soluble B-lymphocyte stimulator (BLyS)
and acts as a specific inhibitor of its
biological activity. BLyS, also known as Bcell activating factor (BAFF) is an
immunomodulatory cytokine that
promotes B-cell survival, B-cell
differentiation, and immunoglobulin class
switching.
The efficacy and safety of Belimumab in

the treatment of lupus patients was
studied in several trials. Two large phase
3 placebo controlled clinical trials (BLISS52 and BLISS-76 of 1684 lupus patients
with mild to moderate disease activity
(without lupus nephritis/CNS)
demonstrated significant clinical
response with 10 mg/kg of Belimumab as
compared to placebo.
Belimumab treatment (at 10 mg/kg) also reduced

SLE-related flares, normalized C3 levels and had a
steroid sparing effect The beneficial effects of
Belimumab over placebo appeared 16e24 weeks
following the initiation of the treatment and
persisted through 52 weeks. Based on the results
of the BLISS trials, Belimumab was approved by
the FDA for the treatment of SLE patients on
March 2011 and became the first drug approved
for SLE for over 50 years. It should be noted that
a large percentage of the patients did not respond
to Belimumab treatment.
Atacicept
a fully humanized fusion protein combining the Fc
portion of IgG and the TACI receptor that binds BLyS
as well as APRIL thus inhibiting both B-cell
stimulating factors. In a phase Ib study (49 patients
with mild to moderate lupus), Atacicept was
reported to be safe, well tolerated and had
beneficial therapeutic effects However, the phase
I/II randomized controlled trial of Atacicept in
patients with lupus nephritis (background treatment
included corticosteroids and Mycofenolate Mofetil)
was prematurely terminated due to safety concerns
(increased proteinuria, severe pneumonia)
Abatacept
The cytotoxic T lymphocyte antigen 4 (CTLA-4) can
bind efficiently to CD80/CD86, thus preventing Tcell co-stimulation via the CD28 pathway.
Abatacept is a fusion protein of CTLA-4 and the Fc
portion of human IgG1 [49].
However, in two placebo controlled clinical trials of
lupus patients (with or without lupus nephritis),
Abatacept treatment was not effective as
compared to placebo [51]. Thus, currently
Abatacept is not approved for lupus treatment,
although some clinicians use it as an off label
agent.
Tocilizumab
(anti IL-6 receptor mAb) IL-6 is a multifactorial proinflammatory cytokine that was shown to play a role in
the pathogenesis and treatment of murine lupus
Moreover, elevated levels of IL-6 were found in sera of
active lupus patients. Tocilizumab is a fully humanized
mAb against the IL-6 receptor that prevents binding of IL6 to both, membrane and soluble receptors. A small
phase I trial (16 lupus patients) suggested that
Tocilizumab is safe and beneficial in SLE .
Further controlled clinical studies are required in order to
evaluate the therapeutic role of Tocilizumab in lupus.
Sirukumab a human anti IL-6 mAb is currently in a phase
II clinical study in patients with lupus nephritis.
Epratuzumab
(Anti-CD22 mAb) CD22 is a 140kD surface protein,
expressed on most mature B cells. It has a role in
controlling B cell responses
humanized IgG1 anti-CD22 mAb, was shown to
reduce the expression of CD22on the surface of
peripheral B cells obtained from healthy donors
and lupus patients. The reduction of those
molecules appears to result from both,
internalization of CD22 (via the F(ab)2 fragment)
and a specific phagocytosis mechanism e transfer
of B cell surface molecules to monocytes and NK
cells via the Fc fragment.
Epratuzumab has unique immunoregulatory

effects. Two studies reported clinical
improvement, compared to placebo, in 14
(phase I) and 90 patients (ALLEVIATE-1/2 trials)
with active lupus disease following
Epratuzumab treatment.
Epratuzumab was well tolerated without
severe adverse events. A 12-week phase IIb
(EMBLEM) randomized, double-blind, placebocontrolled multicenter study was further
conducted with
Epartuzumab. The study included 227

patients with a moderate to severe lupus
disease activity without active renal or
central nervous system involvement.
Treatment with Epratuzumab 2400 mg
cumulative dose was well tolerated and
associated with improvements in disease
activity. Two multinational, phase III trials
(EMBODY), are in progress and should clarify
the actual role of Epratuzumab in the
treatment of lupus patients.
Whats about Stem cell

therapy
Nonmyeloablative hematopoietic stem

cell transplantation for systemic lupus
.erythematosus
RESULTS:
Fifty patients were enrolled and underwent stem cell
mobilization. Two patients died after mobilization, one from
disseminated mucormycosis and another from active lupus after
postponing the transplantation for 4 months. Forty-eight
patients underwent nonmyeloablative HSCT. Treatment-related
mortality was 2% (1/50). By intention to treat, treatment-related
mortality was 4% (2/50). With a mean follow-up of 29 months
(range, 6 months to 7.5 years) for patients undergoing HSCT,
overall 5-year survival was 84%, and probability of disease-free
survival at 5 years following HSCT was 50%. Secondary analysis
demonstrated stabilization of renal function and significant
improvement in SLEDAI score, ANA, anti-ds DNA, complement,
and carbon monoxide diffusion lung capacity adjusted for
hemoglobin.
In treatment-refractory SLE, autologous

nonmyeloablative HSCT results in
amelioration of disease activity,
improvement in serologic markers, and
either stabilization or reversal of organ
dysfunction. These data are
nonrandomized and thus preliminary,
providing the foundation and justification
for a definitive randomized trial.
Allogeneic HSCT started the transplantation

era for SLE.
A retrospective study identified 35 patients
having received 38 allogeneic transplants for
various autoimmune diseases including SLE,
and found that the transplant-related
mortality was 22.1% at 2 years and 30% at 5
years, while death during progression of the
disease was 3.2% at 2 years and 8.7% at 5
years. Therefore, the use of allogeneic
transplant got restricted.
By 2011, more than 200 auto-HSCT had been

reported world-wide for SLE. In patients with severe
SLE refractory to conventional immunosuppressive
therapies, autoHSCT can achieve sustained clinical
remissions (ranging from 50% to 70% disease-free
survival at 5 years) associated with qualitative
immunological changes not seen with other forms of
therapy.
However, this clinical benefit is associated with an
increase in short-term mortality in most studies,
which can be reduced by improving patient selection
and optimizing induction and maintenance therapy.
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SLE What's Going On

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SLE Whats going on

Efficacy and safety of rituximab in the

Rituximab in the Treatment of Shrinking

The efficacy and safety of Belimumab in

Belimumab treatment (at 10 mg/kg) also reduced

Epratuzumab has unique immunoregulatory

Epartuzumab. The study included 227

Whats about Stem cell

Nonmyeloablative hematopoietic stem

In treatment-refractory SLE, autologous

Allogeneic HSCT started the transplantation

By 2011, more than 200 auto-HSCT had been

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