Discussion
Herein, we described a case of TMA due to acquired complement factor I
deficiency in a male receiving interferon-beta treatment for multiple
sclerosis.
The immunomodulatory effect of interferon therapy has been recorded in
the literature to generate autoimmune disorders, particularly with
interferon-alpha, including examples of TMA in chronic myelogenous
leukemia patients where high-dose treatment for a long period has been
advised [5].
With IFNβ, only a few autoimmune signs have been documented even though
it can cause flu-like symptoms, temporary laboratory abnormalities,
menstrual problems, and local dermal injection site responses.
IFNβ-induced TMA has been rarely reported [6].
A few mechanisms have been proposed to explain how interferon causes
TMA, but insufficient immunological studies have been unable to pin this
phenomenon down to a single pathophysiologic pathway [5, 7].
Some authors inferred that complement-mediated TMA was excluded due to
normal complement levels [7]. However, serum complement factor C3
and C4 measurements have poor predictive value in determining the
underlying pathophysiology of TMA [9]. Indeed, during most aHUS
presentations, serum C3 and C4 levels are generally within reference
values [10, 11].
Published literature identified 25 patients who developed TMA with renal
impairment after receiving IFNβ as a disease-modifying treatment
[1].
Orvain et al. [12] described a 52-year-old man who got
TMA-associated severe renal failure due to severe ADAMTS13 insufficiency
as a result of an anti-ADAMTS13 IgG antibody generated during IFN
treatment for multiple sclerosis. Treatment included IFNβ
discontinuation, immediate plasma exchange therapy, corticosteroids, and
hemodialysis. Rituximab was introduced in face of hemolysis relapse.
The patient did not experience hematological relapse but remained
dependent on hemodialysis.
Our case is very similar to that of Orvain et al. except that the
clinical presentation of our patient was compatible with aHUS while the
underlying pathophysiological mechanism was an acquired factor I
deficiency in the context of IFNβ treatment for multiple sclerosis.
Due to its ability to destroy activated complement proteins C3b and C4b
in the presence of cofactors, factor I is a critical inhibitor governing
all complement pathways. Complete lack of factor I, which is mostly
generated in the liver, is uncommon and results in excessive complement
consumption, which can lead to repeated severe infections,
glomerulonephritis, or autoimmune disorders. The incomplete factor I
deficiency, as noted with our patient, is in turn associated with aHUS
[13].
The factor I deficiency in the reported patient doesn’t seem important,
this could be explained by the complement investigation after the
instauration of the treatment but far from the plasma exchange sessions
so as not to distort the result. unfortunately, exploration of the
complement system was not done at the start of support.
In this report, two arguments support the hypothesis of an acquired
incomplete deficiency of factor I due to antibodies generated by IFNβ.
The first is the subsequent normalization of factor I level and the
second is immunoglobulin deposition on kidney biopsy which indicates an
underlying antibody-mediated process.
The state of autoimmunity secondary to IFNβ treatment is on another hand
attested by the presence of anti-neutrophil cytoplasmic antibodies
without specificity in our patient while Orvain et al. found antinuclear
antibodies positivity [12].
Standard treatment with corticosteroids and plasma exchange was
sufficient to control the hemolytic process in the reported case.
Rituximab was necessary to control the situation in some cases reported
in the literature [12, 14].