Introduction
For patients with relapsing-remitting multiple sclerosis (RRMS),
interferon-beta (IFN) is a well-established first-line therapy that is
still commonly administered.
Thrombotic microangiopathy (TMA), a group of microvascular disorders
with diminished organ perfusion and hemolytic anemia, is a rare yet
serious side effect that can arise years after starting IFN therapy
[1].
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome
(HUS) are the two most common diseases associated with TMA. Ischemia in
the brain and other organs is caused by systemic microvascular
aggregation of platelets in TTP. In HUS, platelet-fibrin thrombi mostly
occlude the renal circulation [2].
TTP is specifically caused by a severe deficiency in ADAMTS13 while HUS
is mostly due to a Shiga toxin producing-Escherichia Coli infection. In
10% of the cases, excessive complement activation and membrane attack
complex deposits contribute to atypical HUS (aHUS) when one or more
regulators of the alternative route of the complement (factor H, factor
I, C4b-binding protein, complement receptor 1, CD46) are dysregulated
[3,4].
We report herein, a TMA case due to acquired complement factor I
deficiency in a patient receiving interferon-beta (IFNβ) for multiple
sclerosis.
It’s worth mentioning that there’s relatively little experience with TMA
associated with interferon. Particularly those involving immunological
testing and complement system study, underscoring the need of reporting
such cases today.
Case report
A 28-year-old man was diagnosed with RRMS in 2007. Subcutaneous IFNβ 44
μg was commenced three times a week in 2017. He had no other medical
conditions and received no other treatment.
In July 2020, he was admitted to the intensive care unit for a status
epilepticus associated with severe arterial hypertension and then
transferred to the Nephrology department for management of malignant
arterial hypertension with acute renal failure. On examination, he did
not present any neurological disorder but had very unbalanced blood
pressure under triple therapy. Urine dipstick showed proteinuria +++ and
hematuria +++. Biological investigations showed hemolytic anemia
(hemoglobin at 9.7 g/dL, elevated LDH
level at 3N, low haptoglobin level < 58.3, elevated
reticulocyte count, and presence of schistocytes at 4%), normal
platelet count at 165 G/L, renal failure (creatininemia at 146 µmol/L,
and urea at 9.1 mmol/L) and hypokalemia at 3 mmol/L. Urinary analysis
revealed proteinuria of glomerular origin (7g/day).
Initial immunological investigations showed no complement activation (C3
at 1.08g/l and C4 at 0.32 g/l), undetectable antiphospholipid antibodies
(assays for anti-b2-glycoprotein 1 and anticardiolipin antibodies were
negative and there was no lupus anticoagulant), negative antinuclear
antibodies, negative anti-glomerular basement membrane and positive
anti-neutrophil cytoplasmic antibodies (40, N< 20) with no
specificity.
This clinical-biological presentation strongly evoked aHUS complicating
IFNβ. In addition to treatment discontinuation, the patient received
methylprednisolone of 10 mg/kg intravenous for 3 consecutive days
switched to oral corticosteroid therapy of 0.5 mg / Kg/day and received
supportive treatment including plasma exchange.
Despite the achievement of seven sessions of plasma exchange, the renal
failure rapidly worsened and the patient required hemodialysis. A kidney
biopsy was therefore indicated and was performed three days after
stopping the plasma exchange sessions with a normal hemostasis
assessment.
The renal puncture biopsy showed acute and chronic vascular and
glomerular TMA (mesangiolysis, reduction of the lumen of the glomerular
capillaries, fibrinoid necrosis, mesangial fibrosis, and onion bulb
appearance of vessels) with IgG and fibrinogen deposits in the
immunofluorescence study (Fig 1, 2&3). The biopsy was complicated by
the progressive constitution of a perirenal hematoma leading to a state
of hemorrhagic shock which required embolization of two distal arteries.
The patient subsequently benefited from five other plasma exchange
sessions permitting the regression of the hemolytic process. However,
there was no renal recovery and the patient remained
hemodialysis-dependent.
Far from plasma exchanges, we explored the complement system. The
results were received lately while the hemolytic process was controlled
by standard treatment and showed a decrease in complement factor I:
26,83 mg/l (32,3-87,5). The other proteins of the alternate complement
pathway (factor B, factor H, and MCP) as well as the ADAMTS13 activity
were within the normal range.
Given the absence of recurrence of hemolysis, no other treatment with
rituximab, initially mentioned, was initiated.
At follow-up 6 months later, the patient had not regained kidney
function and the complement factor I rate was still low. He remained on
hemodialysis and was still taking three antihypertensive treatments.
Two years after the initial diagnosis, he did not experience
hematological relapse and remained dependent on hemodialysis. His blood
pressure has normalized without antihypertensive treatment and he was
desiring cadaveric kidney transplantation. The exploration of the
complement system was therefore redone and the activity of factor I was
this time normal at 70% (70-100%).