Efficacy of Rituximab in Successful Management of Refractory Juvenile Systemic Lupus Erythematosus Complicated with Macrophage Activation Syndrome: A Case Report with Literature Overview

Dear Editor, Juvenile systemic lupus erythematosus (jSLE) is an autoimmune disease affecting children younger than 18 years of age, contributing approximately 15%–20% of total systemic lupus erythematosus (SLE) patients.[1] SLE related systemic complications are more in jSLE. Macrophage activation syndrome (MAS) is a life-threatening sequela, with an incidence of 0.9%–4.6%.[2] B cells are recognised to have a major role in developing autoimmunity in SLE. Therefore, novel biologics like Rituximab, a CD20 receptor blocker of B cell can be a promising therapeutic option in jSLE. Hereby we are reporting the therapeutic effect of rituximab in the management of a refractory case of jSLE, complicated with MAS. A 16-year-old female was presented with a 4-week history of fever, abdominal pain, vomiting, malaise, drowsiness having reddish skin rash over cheeks. She had a 3-year history of SLE featuring intermittent fever, arthritis, oral ulcers, leukopenia, positive antinuclear antibodies, Anti-double stranded DNA, anti-smith confirming the diagnosis of SLE as per European league against rheumatism score 26, requiring multiple hospital admissions for frequent disease flares. Upon admission, she was febrile and disoriented. There was erythematous rash studded with crusts present over malar area of face involving the nasal bridge and sparing nasolabial groove, periorbital region. Erythema, crusting, and scaling were also present over scalp with diffuse telogen effluvium. Both soles have purpuric rash with perilesional erythema [Figure 1]. A solitary superficial erosion was present over the hard palate. Laboratory studies showed pancytopenia, reticulocytosis, hyponatremia, elevated liver enzymes, and proteinuria. Further workup showed that she had marked elevated d-dimer, ferritin, lactate dehydrogenase, and triglycerides, prolonged activated partial thromboplastin time, decreased complement levels, and elevated erythrocyte sedimentation rate and c- reactive protein, with positive direct Coombs test. A 24-hour urine protein test demonstrated proteinuria in the subnephrotic range (0.52 g/24 hour). Abdominal ultrasonography confirmed hepatosplenomegaly, while chest X-ray and echocardiography were normal. The SLE Disease Activity Index (SLEDAI-2K) score was 16. Renal biopsy was considered, but postponed due to severe thrombocytopenia. Blood culture sensitivity report came positive for Salmonella group of organisms. Based on the laboratory and clinical findings in accordance with the hemo phagocytic lymphohistiocytosis (HLH) diagnostic criteria, a provisional diagnosis of MAS secondary to SLE flare with bacterial sepsis was made. Intravenous methylprednisolone 1 g/day as pulse therapy (for 3 days) was started along with injectable sensitive antibiotic. Erythema, crusting scaling over the face and scalp was resolved. Purpuric macules over soles turned dusky [Figure 2].Figure 1: (a) Erythematous rash with crusts over malar area involving the nasal bridge and nasolabial groove, periorbital region, part just below the lower lip and philtrum were spared; (b) Scalp showing erythema and crusting with diffuse hair loss; (c) Purpuric rash with perilesional erythema over both solesFigure 2: (a and b) Resolved erythema and crusting over face and scalp (post treatment); (c) Subsiding erythema with purpuric rash over soles (post treatment)The patient was discharged after symptomatic improvement with tapering doses of oral prednisolone. Further patient came back again with a severe disease flare, while on tapering dose of oral steroid 20 mg. Therefore, considering the disease activity and refractoriness to conventional treatment, intravenous Rituximab (as per rheumatoid arthritis protocol) was administered. Oral prednisolone dose was successfully tapered to 20 mg daily that finally stopped within 4 to 5 months of initial cycles of Rituximab. Hydroxychloroquine 200 mg/day was continued with strict photoprotection. One year after the treatment, the patient remains symptom-free without any potential adverse effects. jSLE follow more chronic and protracted course than adult and associated with irreversible organ damage leading to reduced life expectancy of individual child. MAS is an acute lethal outcome of jSLE, that develops due to inadvertent massive cytokine storm which lead to dysregulated hemophagocytosis. MAS secondary to SLE was diagnosed on basis of HLH-2004 diagnostic guidelines.[3] Rituximab is also an effective treatment option for MAS by modifying the cytokine cascade along with both adaptive and innate immunity either as a monotherapy or an adjunct to the HLH-2004 protocol, especially for underlying SLE. SLE patients are also prone for infections due to chronic immunosuppressives use, defective opsonisation system and cell mediated immunity. Salmonella infection is one of the commonest opportunistic infections in lupus patients, like our case. Till date, high dose of systemic glucocorticoids (GC) is the 1st line treatment for rapid disease control in SLE flare because of its potent anti-inflammatory and immunosuppressive effects. However, prolonged use of systemic GC should be avoided in paediatric population due to detrimental effects like growth retardation, osteoporosis, amenorrhea, cushingoid features, hypothalamic-pituitary-gonadal axis suppression with dosages ≥7.5 mg/day. Therefore, steroid sparing therapeutics can be preferred. However, several target specific biologics have proven to be safe and efficacious in the treatment of jSLE. Belimumab, a biologic response modifier, has been approved by United States- Food and drug adminstration in lupus management, but is unavailable in our country till date. As per literatures, Rituximab has also been used safely in various paediatric rheumatologic conditions extensively. Hereby we are enumerating few studies focusing the role of Rituximab in jSLE having aggressive systemic involvement [Table 1].Table 1: Literature reviews depicting role of rituximab in management of jSLEIn our case we also treated the acute SLE flare and MAS initially with intravenous Methylprednisolone pulse followed by tapering dose of oral prednisolone. Meanwhile, on tapering, as the disease got aggravated with deranged haematological parameters, Rituximab was planned. Following this, steroid dose was successfully tapered without further flares. After that patient was well maintained with strict photoprotection and hydroxychloroquine (5 mg/kg). Management of refractory jSLE is a practical challenge in the field of dermatology. However, in the era of biologics, Rituximab can be a safe and efficacious adjunct therapy as autoreactive B-cell has a role in the pathogenesis of SLE. It may help to overcome the adverse effects of conventional immunosuppressive drugs in paediatric population. Although subsequent Randomized controlled trials are further required to establish its long-term efficacy and safety in children. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.