(T1330-10-65) Tocilizumab Induced Immunosuppression in A Case of Adult-Onset Still’s Disease: Are These Newer Biologics Double Edged Sword?

Purpose: Adult-Onset Still’s Disease (AOSD) is a rare multisystemic disorder considered as a complex (multigenic) autoinflammatory syndrome characterized by fever, transient skin rash, arthritis, or arthralgia, increased neutrophils, hepatosplenomegaly, and lymphadenopathy. The etiology is not clearly understood and with wide range of differential diagnosis available, it is difficult to diagnose AOSD. Initial treatment strategy includes use of hands-on drugs like Non-steroidal Anti-inflammatory Drugs, low dose corticosteroids, conventional DMARDs. But as the disease progresses to severe form, targeted and biologic DMARDs could be the option for management. Interleukin-6 being one among the many cytokines involved in the pathogenesis of Adult-Onset Still’s Disease, has made itself a target for the treatment of refractory cases. Tocilizumab, a recombinant humanized anti IL-6 monoclonal antibody, is one such biologic drug available in the market that has proven its therapeutic efficacy in several clinical trials. Adult-Onset Still’s Disease (AOSD) is a rare multisystemic disorder considered as a complex (multigenic) autoinflammatory syndrome characterized by fever, transient skin rash, arthritis, or arthralgia, increased neutrophils, hepatosplenomegaly, and lymphadenopathy. The etiology is not clearly understood and with wide range of differential diagnosis available, it is difficult to diagnose AOSD. Initial treatment strategy includes use of hands-on drugs like Non-steroidal Anti-inflammatory Drugs, low dose corticosteroids, conventional DMARDs. But as the disease progresses to severe form, targeted and biologic DMARDs could be the option for management. Interleukin-6 being one among the many cytokines involved in the pathogenesis of Adult-Onset Still’s Disease, has made itself a target for the treatment of refractory cases. Tocilizumab, a recombinant humanized anti IL-6 monoclonal antibody, is one such biologic drug available in the market that has proven its therapeutic efficacy in several clinical trials.

Methods: We are presenting a case of 37 year old female patient, known case of AOSD for 4 years. Patient was initially maintained on low dose corticosteroid and conventional DMARD like Hydroxychloroquine and Methotrexate. Flare ups of the disease warranted the use of Tocilizumab and Tofacitinib in this patient. After clinical as well as pathological improvement with Tocilizumab 2 years before, signs of immunosuppression were observed when tocilizumab was reintroduced (560 mg) one month before the admission for the treatment. Patient suffered from Acute Pyelonephritis, Septicemia, Shock, Oropharyngeal Candidiasis and Bronchitis which could be owned to immunosuppressive action of Tocilizumab. On the day of admission, her vitals were: Temp. was normal, Pulse- 123/min, B.P.- 82/44 mm Hg and Oxygen saturation was 95% on room air. Her lab investigations revealed Haemoglobin –10.3 g/dl, Total W.B.C.– 38020/cu mm with Neutrophils- 93%, Lymphocytes-03%, Eosinophils-00%, Monocytes-04%, Basophils-0%, Total platelet count- 185000/cu mm, S. Creatinine-1.77 mg/dL, S. sodium- 132.38mEq/L, S. potassium-3.26mEq/L, S. chloride- 96.99mEq/L, Procalcitonin- 81.36 ng/ml, CRP-146.55 mg/L, S.G.P.T.-16 U/L, S.G.O.T.-56.71U/L. Urine analysis revealed presence of Albumin, 8-10 pus cells and few granular casts. No organisms were isolated from urine culture. X-Ray Chest PA view was normal. USG Whole Abdomen showed “Raised cortical echo pattern of both kidneys with preserved cortico-medullary differentiation, suggesting possibility of Renal Parenchymal Disease/ Changes of Pyelonephritis.” Patient was treated with IV fluids, antacids, antiemetics and antibiotics. During the hospital stay, patient developed oral candida infection, which was treated with IV Fluconazole and Bronchitis, which was treated with IV antibiotic. Throat swab culture revealed presence of Klebsiella pneumoniace. After 10 days of hospitalization, patient’s S. Creatinine level was within range, Total WBC count was decreased, and fungal infection subsided. Subsequently patient was discharged. On discharge medication included Tab. Prednisolone 10 mg in morning and 5mg in night and other supportive treatment.

Results: The above case has been reported as ‘Tocilizumab induced Septicaemia’ under unique ID number IN-IPC-300641246 to Indian Pharmacopoeia Commission. As the reaction follows temporal relationship and it can also be explained by other drugs, causality assessment of this ADR is “Possible”.

Conclusion: One can reduce the chances of infection and other adverse effects by careful periodic monitoring of various laboratory parameters like Total W.B.C., Total platelet count and Liver enzymes. Cautious selection of the patient is needed for the treatment with newer biologic agents. As per The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis and U.S. F.D.A. approved medication guide for usage of Tocilizumab (ACTEMRA), such infections can be prevented by pre-treatment screening for infections as well as regular monitoring of Total W.B.C. count while using these drugs.

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Table-1: Lab Investigations of patient on follow up during admission