\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Thrombotic microangiopathy due to acquired complement factor I
deficiency in a male receiving interferon-beta treatment for multiple
sclerosis}



\author[1]{sanda mrabet}%
\author[1]{Rihem Dahmane}%
\author[1]{Raja Boukadida}%
\author[1]{Asma Fradi}%
\author[1]{Narjess Ben Aicha}%
\author[2]{Wissal Sahtout}%
\author[2]{Awatef Azzabi}%
\author[1]{Yosra Guedri}%
\author[1]{Dorsaf Zellama}%
\author[1]{Abdellatif Achour}%
\author[3]{Imen  Sfar}%
\author[4]{Rim Goucha}%
\author[5]{Nihed Abdessayed}%
\author[5]{Moncef Mokni}%
\affil[1]{Sahloul University Hospital}%
\affil[2]{Affiliation not available}%
\affil[3]{Charles Nicolle Hospital}%
\affil[4]{La Marsa Internal Security Forces Hospital}%
\affil[5]{Farhat Hached University Hospital of Sousse}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Interferon-beta, the most widely prescribed medication for multiple
sclerosis, is generally considered safe. Nevertheless, rarely serious
and/or life-threatening side effects have been reported such as
thrombotic microangiopathy. A few mechanisms have been proposed to
explain how interferon causes thrombotic microangiopathy, but
insufficient immunological studies have been unable to pin this
phenomenon down to a single pathophysiologic pathway. We report
thrombotic microangiopathy due to acquired complement factor I
deficiency in a male receiving interferon-beta treatment for multiple
sclerosis. After three years of starting the therapy, the 28-year-old
patient presented with malignant hypertension causing seizures, rapidly
progressive renal failure requiring hemodialysis, and hemolytic anemia.
Corticosteroid and plasma exchange sessions permitted hemolysis control.
Nonetheless, the patient remained hemodialysis-dependent. Exploration of
the complement system found a complement factor I deficiency whose
activity normalized at the control carried out after two years. We
concluded that IFN\selectlanguage{greek}β \selectlanguage{english}treatment may cause complement factor I deficit,
which can lead to thrombotic microangiopathy and severe renal failure.%
\end{abstract}%



\sloppy


\textbf{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 (IFN\selectlanguage{greek}β\selectlanguage{english}) 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.

\textbf{Case report}

A 28-year-old man was diagnosed with RRMS in 2007. Subcutaneous IFN\selectlanguage{greek}β \selectlanguage{english}44
\selectlanguage{greek}μ\selectlanguage{english}g 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 \textless{} 58.3, elevated
reticulocyte count, and presence of schistocytes at 4\%), normal
platelet count at 165 G/L, renal failure (creatininemia at 146 \selectlanguage{greek}µ\selectlanguage{english}mol/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\textless{} 20) with no
specificity.

This clinical-biological presentation strongly evoked aHUS complicating
IFN\selectlanguage{greek}β. \selectlanguage{english}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\%).

\textbf{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 IFN\selectlanguage{greek}β, \selectlanguage{english}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.
IFN\selectlanguage{greek}β-\selectlanguage{english}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 IFN\selectlanguage{greek}β \selectlanguage{english}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 IFN\selectlanguage{greek}β
\selectlanguage{english}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 IFN\selectlanguage{greek}β \selectlanguage{english}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 IFN\selectlanguage{greek}β.
\selectlanguage{english}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 IFN\selectlanguage{greek}β \selectlanguage{english}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{]}.

\textbf{Conclusion~}

IFN\selectlanguage{greek}β \selectlanguage{english}treatment can cause complement factor I deficit, which can lead to
a life-threatening TMA and severe renal failure. Hence, IFN\selectlanguage{greek}β \selectlanguage{english}should be
stopped and corticosteroids and plasma exchange therapy began promptly.
Exploration of the complement system should be considered in the face of
a clinical-biological presentation of IFN\selectlanguage{greek}β-\selectlanguage{english}induced TMA to clarify the
diagnosis.

In cases of the resistant or relapsing disease, rituximab should be
investigated.

\textbf{Acknowledgements}

None

\textbf{Data availability}

Data are available on request from the corresponding author.

\textbf{Funding}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Conflict of interest disclosure}

The authors have no conflict of interest to declare.

\textbf{Ethical approval}

Given the nature of the article, a case report, no ethical approval was
required.

\textbf{Consent}

Written informed consent was obtained from the patient for publication
of this case and accompanying images. A copy of the written consent is
available for review by the Editor-in-Chief of this journal on request.

\textbf{Permission to reproduce material from other sources}

No material has been reproduced from other works.

\textbf{Clinical trial registration}

This does not apply as it is a case report of a patient who has given
written consent and has been de-identified. It is therefore not
prospective research involving human participants.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Parisi M, Manni A, Caputo F, Trojano M, Paolicelli D. A case report of
  late-onset atypical Hemolytic Uremic Syndrome during interferon-beta
  in multiple sclerosis: Open issues in literature review. \emph{Brain
  Behav} . 2021~; 11(1)~:e01930.
\item
  Caprioli J, Remuzzi G, Noris M. Thrombotic microangiopathies: from
  animal models to human disease and cure. \emph{Contrib Nephrol} .
  2011~; 169:337-350.
\item
  Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic
  purpura.\emph{Blood} . 2017~; 129(21)~:2836-2846.
\item
  Jlajla H, Denman F, Jallouli M, et al. Molecular basis of complement
  factor I deficiency in Tunisian atypical hemolytic and uraemic
  syndrome patients. \emph{Nephrology (Carlton)} . 2019~;
  24(3)~:357-364.
\item
  Zuber J, Martinez F, Droz D, Oksenhendler E, Legendre C~; Groupe
  D'stude Des Nephrologues D'ile-de-France (GENIF).
  Alpha-interferon-associated thrombotic microangiopathy: a
  clinicopathologic study of 8 patients and review of the
  literature.\emph{Medicine (Baltimore)} . 2002~; 81(4)~:321-331.
\item
  Walther EU, Hohlfeld R. Multiple sclerosis~: side effects of
  interferon-beta therapy and their management. \emph{Neurology} .
  1999~; 53(8)~:1622-1627.
\item
  Broughton A, Cosyns JP, Jadoul M. Thrombotic microangiopathy induced
  by long-term interferon-\selectlanguage{greek}β \selectlanguage{english}therapy for multiple sclerosis: a case
  report. \emph{Clin Nephrol} . 2011~; 76(5)~:396-400.
\item
  Yam C, Fok A, Mclean C, Butler E, Kempster P. Interferon-beta in
  multiple sclerosis causing thrombotic microangiopathy. \emph{Intern
  Med J} . 2019~; 49(2)~:274-276.
\item
  Fox LC, Coney SJ, Kausman JY, Shortt J, Hughes PD, Wood EM, et al.
  Consensus opinion on diagnosis and management of thrombotic
  microangiopathy in Australia and New Zealand. \emph{Intern Med J} .
  2018~; 48:624-36.
\item
  Loirat C, Fr\selectlanguage{ngerman}éOrganicBacchi V. Atypical hemolytic uremic
  syndrome.\emph{Orphanet J} \emph{Rare Dis} .2011~; 6: 60.
\item
  de Malmanche T. Routine complement blood tests are insensitive for
  alternative complement activation. \emph{Intern Med J} . 2019~;
  49(8)~:1057-1058.
\item
  Orvain C, Augusto JF, Besson V, et al. Thrombotic microangiopathy due
  to acquired ADAMTS13 deficiency in a patient receiving interferon-beta
  treatment for multiple sclerosis. \emph{Int Urol Nephrol} . 2014~;
  46(1)~:239-242.
\item
  Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM. Complement
  factor I in health and disease. \emph{Mol Immunol} . 2011~;
  48(14)~:1611-1620.
\item
  Gerischer, L. M., Siebert, E., Janke, O., Jungehuelsing, G. J., \&
  Ruprecht, K. (2016). Favorable outcome of interferon-beta associated
  thrombotic microangiopathy following treatment with corticosteroids,
  plasma exchange and rituximab: A case report. \emph{Multiple sclerosis
  and related disorders} , \emph{10} , 63--65.
\end{enumerate}

\textbf{Figure legends~:}

\textbf{Figure 1~:} Mesangial fibrosis with mesangiolysis and reduction
of the lumen of glomerular capillaries (Trichrome stainingx40).

\textbf{Figure 2~:} Segmental fibrinoid necrosis in a glomerulus
(Trichrome stainingx40).

\textbf{Figure 3~:} Onion bulb appearance in medium-caliber vessels
(Trichrome stainingx40)

\textbf{Hosted file}

\verb`figures.docx`  available at \url{https://authorea.com/users/495238/articles/577040-thrombotic-microangiopathy-due-to-acquired-complement-factor-i-deficiency-in-a-male-receiving-interferon-beta-treatment-for-multiple-sclerosis}

\selectlanguage{english}
\FloatBarrier
\end{document}

