Discussion and Conclusion
One of the main side effects of rituximab are infusion reactions which mainly consist of cytokine release syndrome and in some cases, type I hypersensitivity reaction. (1). Cytokine release syndrome is an overreaction of T lymphocytes that leads to an increased release of certain cytokines (interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF), and interferon (INF)) especially IL-6. Lab work may reveal azotemia, hyperbilirubinemia, and elevated D-dimer levels. CRS symptoms mainly consist of rash, fever, myalgia, arthralgia, nausea, vomiting, diarrhea, tachycardia, tachypnea, headache, confusion, mental change, and seizure.(6,7). Infection with Covid-19 also induces CRS by massive release of cytokines sometimes stated as a “cytokine storm“(8). Tocilizumab is considered one of the drugs for treating CRS.(9)
In our case, middle aged man who was diagnosed with MS, was started on rituximab. After the first dose the patient had shown signs of CRS, however, due to its rare prevalence, management was done based on a diagnosis of moderate allergic reaction. After the second dose of rituximab the patients had presented with similar symptoms, although more severe.
Neurologic side effects such as mental status changes can appear during or after other signs and symptoms. (10). CRS has been classically associated with therapeutic monoclonal antibody infusions, most notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), and anti-CD20 (rituximab).(11).
An important differential diagnosis of CRS is capillary leak syndrome, serum sickness (type III hypersensitivity reaction) (12), and idiopathic infusion reaction. Capillary leak syndrome is a massive leakage of fluid into the interstitial space secondary to increased permeability of vessels mediated by released interleukins that leads to sudden hypotension and shock. Other features may include generalized edema, hemoconcentration and hypoalbuminemia. It is mainly seen in patients with sepsis.(4). There are also reports of capillary leak syndrome in NMO patients treated with rituximab(13).
The overlap between CLS and CRS mandates differentiation of these two syndromes when approaching patients. Capillary fluid leakage is seen in both syndromes but the leakage in CLS is so severe that causes hypotension and shock. Cytokine release syndrome mostly starts with fever, rash, and malaise and is rarely associated with shock. However, hypotension can occur in the course of the disease leading to capillary leak syndrome.(7)
Although rituximab induced cytokine release syndrome has been reported in the treatment of certain diseases(13), this syndrome is very rare in MS patients being treated with the drug. Monoclonal antibodies such as rituximab are now being widely used to treat MS and all side effects of the drug should be assessed and differentials should be recognized when adverse effects occur. Therefore cautious use of the drug in this subset of patients is advised.