Age: 41.0
Sex: F
Vaccine: PPV, TTOX
Symptoms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Biopsy kidney abnormal, Blood alkaline phosphatase normal, Blood bilirubin normal
Clinical narrative: This 41 year old female subject was enrolled in a study for systemic lupus erythematous. The subject took intravenous infusion belimumab 10 mg/kg cyclic from 03 December 2012 and pneumococcal and tetanus vaccine on 05 November 2012, single dose. Medical conditions at the time of the event included hypertension and mitral valve prolapse. Concomitant medications included hydroxychloroquine sulphate, prednisone, metoprolol, rosuvastatin calcium, citalopram hydrobromide, clonazepam, benazepril hydrochloride and triamcinolone. On 04 January 2013, 18 days since the start of belimumab and 60 days after the Pneumococcal vaccine and tetanus vaccine injection and 18 days after the most recent dose of belimumab, the subject developed grade 3 or severe bronchitis, grade 3 or severe acute on chronic renal failure, grade 3 or severe hepatitis and grade 3 or severe hyperkalemia. The subject experienced coughing with sore throat on 25 December 2012. The subject was hospitalised. The subject was treated with azithromycin. Treatment with belimumab was interrupted. Diagnostic included on 04 January 2013- Chest PA/lateral dual energy subtracted soft tissue and bone images- Enlarged cardiopericardial silhouette with pulmonary venous hypertension without frank edema, focal pneumonia or pleural disease. 05 January 2013- Ultrasound abdomen limited- Mild hepatomegaly and Renal sonogram- stable slightly echogenic kidneys bilaterally, a non specific indicator of renal disease. Otherwise normal renal sonogram. White blood cell count was 12,400 with 14% monocytes. On 04 January 2013, creatinine was up 3.6 from her baseline of 1.5. Alanine aminotransferase was 838, Aspartate aminotransferase was 959, and alkaline phosphatase and bilirubin were normal. Potassium was up to 5.9. Reference range and units were not provided for diagnostics. Outcome was unknown at time of reporting. The investigator considered that there was no reasonable possibility that the bronchitis, acute on chronic renal failure, hepatitis and hyperkalemia may have been caused by belimumab, Pneumococcal vaccine and tetanus vaccine. Follow-up received on 11 January 2013: The bronchitis resolved on an unknown date. The acute on chronic renal failure had not resolved. Hepatitis improved and hyperkalemia resolved on 10 January 2013. 08 January 2013- Renal biopsy was done. Hydroxychloroquine was on hold due to transaminitis. The subject was treated with methylprednisolone. The subject was discharged on 10 January 2013 with prednisone and CELLCEPT. Alanine aminotransferase on 10 January 2013 was 292 and Aspartate aminotransferase was 41. Potassium on 10 January 2013 was 5. Additional information received via the medical monitor on 28 January 2013: AST had returned to normal as of 10 January 2013 however, ALT was still elevated at 292. Creatinine is at 2.7. Blood counts were normal. Negative HBsAg, HCV Ab, liver ultrasound showed hepatomegaly and echotexture. During the hospitalization the subject was treated for an acute lupus flare with significant drop in C4, C3 and confirmed active nephritis on a repeat biopsy. The transaminase elevations were most likely due to the lupus flare. CMV antigen and PCR study was requested. Further dosing was held. The cough/dyspnea was likely pulmonary congestion from her underlying cardiac dysfunction as she had severe mitral stenosis and not "bronchitis". Chest x-ray showed just PVH and cardiomegaly and no infiltrates. The subject was treated with azithromycin several days prior to her admission with the AST and ALT elevations and acute on chronic renal failure. There was no prior history of hepatitis other than the passive congestion which she had a previous CHF decompensation. She had a previous history of lupus nephritis that was treated with CTX and mycophenolate, none recently until put back on mycophenolate last month for evidence of active lupus flare (very low C3 C4). Renal biopsy showed class IV-CIV-G 60% glomeri globally sclerotic or focal scarred no activity in the lesion. There was no known precipitating events that caused the SLE flare. The investigator was not sure of the cause of the AST, ALT elevations -hepatic congestion vs drug effect from the azithromycin vs viral vs autoimmune flare (although no prior hx of this). Follow-up received on 11 February 2013 from medical monitor: Past medical history included hyperkalemia, volume overload and renal insufficiency. Conditions also included proteinuria, pericardial effusion, arthralgia and photosensitivity. Possible bronchitis resolved on 10 January 2013. The subject did not have bronchitis symptoms attributable to CHF. The acute on chronic renal failure and hyperkalemia was attributable to CHF. The hepatitis was due to the CHF and medication effect. Follow-up received on 29 April 2013: Medical conditions present at the time of the event included lupus nephritis and mitral valve stenosis. On 04 January 2013, 18 days since the start of belimumab and 60 days after the Pneumococcal vaccine and tetanus vaccine injection and 18 days after the most recent dose of belimumab, the subject developed grade 3 or severe congestive heart failure. The event of bronchitis was deleted as the subject did not have bronchitis. Symptoms were attributed to congestive heart failure (CHF). An updated event term of chronic renal failure was provided, previously reported as acute on chronic renal failure. An updated event term of transaminitis was provided, previously reported as hepatitis. The subject was hospitalized. Diagnostic testing on 06 January 2013 included an electroencephalogram (EEG) which showed sinus bradycardia, possible LAE. On 07 January 2013, an echocardiogram showed elevated PA pressure, RV dilation, ejection fraction 50 percent and CHF class II. Renal biopsy from 08 January 2013 showed fibrosis, no activity, minimal immune deposits. Concomitant medications included ferrous sulfate, Vitamin D calcium, cholecalciferol, bisacodyl, mycophenolate mofetil, ondansetron hydrochloride, LORTAB, paracetamol, docusate sodium, salbutamol sulphate, hydralazine, clonidine, multivitamins, methylprednisolone sodium succinate, heparin, sodium chloride, calcium gluconate, dextrose, sorbitan sesquioleate and seasonal trivalent influenza vaccine Dresden. Treatment with belimumab was interrupted. The event of transaminitis resolved on 04 February 2013. At the time of reporting, the event of chronic renal failure was unresolved and the outcome of the event of congestive heart failure was unknown. The investigator considered that there was no reasonable possibility that the chronic renal failure and hyperkalemia may have been caused by belimumab, Pneumococcal vaccine and tetanus vaccine and that the events were possibly due to congestive heart failure. The investigator considered that there was no reasonable possibility that the transaminitis may have been caused by belimumab, Pneumococcal vaccine and tetanus vaccine and that the event was possibly due to congestive heart failure medication effect. The investigator's causal assessment for the event of congestive heart failure was unknown at the time of reporting.