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\begin{document}

\title{Serum Sickness Following Rituximab Therapy in a Patient with Pemphigus
Vulgaris: A Case Report}



\author[1]{Mohamad  Khatib}%
\author[1]{Solaiman  Allafi}%
\author[1]{Abdulqadir Nashwan}%
\affil[1]{Hamad Medical Corporation}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Serum sickness, a reaction presenting with a classic triad (fever, rash,
myalgia/arthralgia) and considered as a rare adverse event following
monoclonal antibodies and specifically following treatment with
rituximab. This report describes a case of serum sickness in a newly
treated young male patient with rituximab for pemphigus vulgaris.%
\end{abstract}%



\sloppy


\textbf{Key Clinical Message}

Clinicians should be vigilant for potential acute or delayed serum
sickness as possible adverse reactions to weigh the benefits and risks
of rituximab therapy in patients with pemphigus vulgaris.

\textbf{Background}

Monoclonal antibodies have been used for the modulation of immune
responses in several disorders, including cancer, autoimmune, and
infectious diseases. \textsuperscript{1}

Rituximab (RTX) is a chimeric monoclonal antibody that specifically
binds to the B-cell surface antigen CD20 which mediate cytotoxicity in
these cells. \textsuperscript{2-4} The mechanism of action of RTX
including, regulating cell-cycle signaling, inducing apoptosis,
improving cytotoxic drugs cells' sensitization, antibody-dependent
cellular, and complement-mediated cytotoxicity. \textsuperscript{4}

RTX is used in the management of previously untreated or treated adults
with CD20+ chronic lymphocytic leukemia (CLL) \textsuperscript{5},
granulomatosis with polyangiitis \textsuperscript{6}, microscopic
polyangiitis \textsuperscript{7}, non-Hodgkin
lymphomas\textsuperscript{8}, pemphigus vulgaris \textsuperscript{9},
rheumatoid arthritis \textsuperscript{10}, and other off-label uses such
as acquired thrombotic thrombocytopenic purpura \textsuperscript{11},
Waldenstr\selectlanguage{ngerman}öm macroglobulinemia \textsuperscript{12}, refractory
autoimmune hemolytic anemia \textsuperscript{13}, etc.

As a monotherapy, RTX (1000 mg) is administered weekly for one month or
every 3 to 4 weeks when used in combination with
chemotherapy.\textsuperscript{14}

Pemphigus is one of the autoimmune diseases which characterized by
cutaneous blisters and erosions and mediated by autoantibodies.
Pemphigus Vulgaris (PV) is the major progressive subtype of pemphigus
and may lead to death if it is not treated. \textsuperscript{15}

The adverse events of RTX might be early (e.g., fever, cough, and
dyspnea), or late such as agranulocytosis or severe
infection.\textsuperscript{16}

Serum sickness is an uncommon hypersensitivity undesirable~reaction due
to antigens, characterized by fever, rash, and
arthralgia.\textsuperscript{17} RTX is induce serum sickness by
producing human anti-chimeric antibodies. \textsuperscript{18} Although
serum sickness is commonly reported in patients with autoimmune disease,
few reports were published for patients with PV.

\textbf{Case Presentation}

A 33\selectlanguage{english}-year\selectlanguage{english}-old male was admitted with a history of fever, malaise,
arthralgia, and myalgia for one day. Two weeks ago, he was started on
RTX (1000mg IV 2 times per week) for the treatment of severe pemphigus
vulgaris in addition to his previous treatment with intravenous
immunoglobulin (IVIG) (2 g/kg per cycle), azathioprine (2.5 mg/kg), and
prednisolone (2 mg/kg per day) which were started earlier. The symptoms
appeared 11 days after the second dose.

Subsequent physical examination revealed fever (a temperature of
38.5degC), hemodynamic instability with sinus tachycardia of 130 - 140
bpm, mild tachypnea, malaise, generalized body rash (cutaneous
blisters), and generalized body pain. He reported severe pain while
moving his elbows, shoulders, knees, wrists, ankles, spine,
metacarpophalangeal joints, and temporomandibular joints. However, no
effusions, swelling, and erythema were noted. He was immediately started
on a wide-spectrum antibiotic at the beginning in view of suspected
sepsis and was discontinued shortly after admission.

Subsequent laboratory investigations revealed leukocyte count 26.4 (4 --
10 x10\^{}3/uL), neutrophils 84.3\%, platelet count 267 (150 -- 400
x10\^{}3/uL), erythrocyte count 6.4 (4.5 -- 5.5 x10\^{}6/uL), C-reactive
protein level 112 (0.0 -- 5.0 mg/L), uric acid level 7.7 (3.4 -- 7.0
mg/dL), creatinine 144 (62 -- 106 umol/L). Coagulation profile,
electrolytes, C3 and C4 levels within normal ranges, Urinalysis was
within normal range except a trace of blood, and blood cultures and
viral panel were negative.

Based on the medication history, physical examination, and excluding
other potential causes; the patient was initially diagnosed with acute
serum sickness associated with RTX therapy. Instantly, he was treated
with methylprednisolone of 1mg/kg/day divided to 2 doses, ample
analgesia with paracetamol, morphine, and fentanyl patches. He was
immediately started on a wide-spectrum antibiotic at the beginning in
view of suspected sepsis and was discontinued shortly after admission.
His signs and symptoms resolved within 2 days from initiation of the
above-mentioned treatment, his follow-up laboratory test results were
normal. Four days later, he was discharged home and referred to a
dermatology and allergy clinic where the treating physician has
discussed with the primary physician the treatment options and possible
complications for resuming the patient on RTX.

\textbf{Discussion}

Rituximab is a novel therapeutic agent for severe and recalcitrant
pemphigus vulgaris (PV). \textsuperscript{19} In patients with PV, human
antichimeric antibodies (e.g., RTX) are known to cause treatment failure
and adverse effects especially with intravenous
administration\textsuperscript{20}.

Rituximab-induced serum sickness (RISS) has been reported earlier in
various autoimmune disorders including rheumatoid arthritis, Sjogren's
syndrome, and hematological malignancies \textsuperscript{21}.
Typically, it has been explained by the presence of the murine component
in RTX and B-cell lysis by forming complexes with antibodies due to the
delivery of intracellular antigens to the serum which then precipitates
systematically in the synovial membranes of joints \textsuperscript{22,
23}.

A 2015 literature review identified 33 reported cases associated with
RTX where most of the reported cases were related to an underlying
rheumatologic condition (such as Sjogren's syndrome). The classic triad
(fever, rash, and arthralgia) of serum sickness was reported less than
half of cases. The mean time from exposure to symptom onset with the RTX
first dose was almost double compared to the second
dose.\textsuperscript{24}

A recent study has described the epidemiological and clinical
characteristics of 37 cases of RISS reported in France. Serum sickness
occurred mainly 12 days after the first injection (54\%). The most
frequent manifestations were rheumatologic symptoms (92\%), fever
(87\%), and skin lesions (78\%). The incidence was significantly higher
when RTX was used for autoimmune diseases than for hematological
malignancies. \textsuperscript{25}

The role of RTX in severe refractory PV has been studied in the past few
years. Some of the documented adverse effects include severe infections
such as pneumonia, progressive multifocal leukoencephalopathy,
anaphylaxis, Stevens-Johnson syndrome. \textsuperscript{19}

In our case, the treating physician did not recommend resuming RTX to
prevent any further severe reaction. Mainly, the diagnosis of serum
sickness depends on clinical features. Other causes such as malignancy
and any infection that can trigger serum sickness should be ruled out.
In this case, investigations such as blood investigations (e.g., CBC,
complement C3, C4, blood culture. etc.), ultrasonography abdomen, and
urine analysis helped in ruling out malignancy and infectious potential
causes. In our patient, clinical presentation, medication history, and
quick response to treatment helped in making the diagnosis of RISS.
Overall, all the clinical features, laboratory findings, quick response
to corticosteroids were suggestive of serum sickness due to RTX (which
was started two weeks ago) after excluding other possible causes.

\textbf{Conclusion}

Rituximab is considered an important treatment option in patients with
moderate to severe refractory pemphigus vulgaris. RTX has been shown to
be effective and well-tolerated in several autoimmune conditions.
However, there are still concerns about its long-term adverse effects.
Clinicians should be vigilant for potential acute or delayed serum
sickness as possible adverse reactions to weigh the risks and benefits
of continuing/reintroducing RTX for patients with pemphigus vulgaris.
Further studies reporting the adverse effects of RTX are required to
establish its safety and tolerability.

\textbf{Abbreviations}

RTX: Rituximab

PV: Pemphigus Vulgaris

IVIG: Intravenous Immunoglobulin

RISS: Rituximab-induced serum sickness

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

The article describes a case report. Therefore, no additional permission
from our Ethics Committee was required.

\textbf{Consent for publication}

The consent for publication was obtained.

\textbf{Availability of data and material}

All data generated or analyzed during this study are included in this
published article.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

This study was not funded.

\textbf{Authors' contributions}

MYK, SMA, AJN: Data Collection, Literature Search, Manuscript
Preparation

All authors read and approved the final manuscript

\textbf{Acknowledgments}

We thank the patient for allowing us to share his case. Open Access
funding provided by the Qatar National Library

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