Tumor Necrosis Factor-alpha Antagonists in the Treatment of Secondary Amyloidosis Gulen Hatemi Istanbul University
TNF-alpha blockage in AA amyloidosis TNF induces SAA production in hepatocytes during the acute phase of inflammation Induces the production of IL-1 and IL-6 Recombinant TNF enhances amyloid deposition in Syrian hamster TNF favors the expression of receptors for advanced glycation products whose interaction with amyloid fibrils is responsible for cytotoxicity and tissue damage. TNF blocking might both reduce the sythesis of amyloid precursers and slow amyloid deposition Gottenberg JE et al. Arthritis nd Rheumatism, 2003
OBJECTIVE To retrospectively evaluate the efficacy and safety of TNFα antagonists in a group of secondary amyloidosis patients treated for up to 7 years in a single center.
PATIENTS Secondary amyloidosis patients treated with TNFα antagonists between April 2001 and March 2008. Only those patients with biopsy proven amyloidosis were surveyed. Both patients who were prescribed TNFα antagonists for amyloidosis and those who were prescribed TNFα antagonists for their diseases and developed amyloidosis during the course of treatment were included.
METHODS Patient charts were surveyed for: Primary diseases, Disease and treatment duration, Previous and concomitant medications, Serum creatinine levels, proteinuria, erythrocyte sedimentation rate and CRP levels during treatment, Number of patients whose creatinine levels and proteinuria improved, stabilized or progressed during treatment, Adverse events. Stable was defined as levels ± 0.3 mg/dl for serum creatinine compared to baseline and ± 0.5 gm/day for proteinuria
RESULTS 32 patients M:F 22:10 Mean age at onset of anti-tnf: 36.7 ± 12.3 years Mean disease duration: 13.8 ± 8.1 years Duration of amyloidosis before anti-tnf (time since the diagnosis of biopsy proven amyloidosis): 2.3 ± 3.8 years Anti-TNF was started immediately after the diagnosis of amyloidosis in 14 patients
Diagnosis of amyloidosis was by: Rectal biopsy: 18/32 Renal biopsy: 8/32 Skin biopsy: 1/32 Lymph node biopsy 1/32 Large bowel biopsy: 1/32 Stomach biopsy: 1/32 Minor salivary gland biopsy: 1/32 Only 1 patient had immunohistochemistry. Amyloidosis was shown with Congo red staining in the others
Primary Diagnoses JIA: 9 patients (5 systemic, 4 polyarticular) FMF: 3 patients FMF + JAS: 2 patients FMF + JIA: 2 patient FMF + AS + Crohn s dis: 1 patient AS: 6 patients RA: 4 patients Behçet s syndrome: 3 patients Crohn s disease: 1 patient Adult onset Still disease: 1 patient
TNFα Antagonists: Infliximab: 17 5 mg/kg: 12 patients 3 mg/kg: 5 patients 0.2.6. Wks q 8 weeks (11 patients) 0.2.6. Wks q 6 weeks (5 patients) 0.2.6. Wks q 4 weeks (1 patient)
TNFα Antagonists: Etanercept: 8 patients Infliximab Etanercept Adalimumab: 2 patients Infliximab Etanercept: 2 patients Etanercept Infliximab: 1 patient Etanercept Adalimumab: 1 patient Infliximab Etanercept Infliximab: 1 patient Duration of treatment: 25.3 ± 23.4 months (4-84 months)
Other Drugs Previous medication (n) Concomitant medication (n) Methotrexate 11 14 Sulfasalazine 14 3 Hydroxychloroquine 5 2 Leflunomide 4 3 Cyclophosphamide 2 0 Azathioprine 5 3 Colchicine 14 20 Prednisolone 16 15 NSAİİ 18 9 ACE inhibitors 1 9 Eprodisate 0 1 Thalidomide 2 1 Gold 1 0
Outcome 20 patients are continuing treatment 5 patients discontinued using TNFα antagonists 6 had died 1 lost to follow-up 4 patients progressed to end stage renal disease 2 had discontinued TNFα antagonists before ESRD developed 1 developed ESRD during treatment with TNFα antagonists 1 died 3 months later with sepsis
WITHDRAWALS 5 patients discontinued anti-tnfα therapy because: Financial reasons: 2 Developed rheumatoid vasculitis: 1 End stage renal disease: 1 Anaphylactic reaction: 1
Efficacy Efficacy was evaluated among those who were treated for > 6 mo: 28 patients: M:F 20:8 Mean age at onset of TNFα antagonists: 35.4 ± 11.8 years Mean disease duration: 13.2 ± 7.9 years Duration of biopsy proven amyloidosis before anti-tnf: 2.2 ± 3.2 years
Serum creatinine 2,4 Mean serum creatinine 2,2 2,0 Baseline: 1.14 ± 0.59 mg/dl Last: 1.67 ± 1.34 mg/dl Increased 10/28 Mean serum creatinine 1,8 1,6 1,4 1,2 1,0,8 N = 28 Initial 28 Last Stable 17/28 Decreased 1/28 p = 0.01
Serum creatinine Serum creatinine 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 1 3 5 7 9 11 13 15 17 19 21 23 25 every 3-4 months
Serum creatinine Serum creatinine 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 1 3 5 7 9 11 13 15 17 19 21 23 25 every 3-4 months
Serum creatinine Cr <1.5 mg/dl (n = 20) Cr 1.5 mg/dl (n = 8) Baseline Cr 0.82 ± 0.24 1.95 ± 0.39 Last Cr 1.2 ± 1.02 2.85 ± 1.36 p 0.085 0.059 Increased 5/20 (25%) 5/8 (63%) Stable 15/20 (75%) 2/8 (25%) Decreased - 1/8 (13%)
Proteinuria 5,0 Mean proteinuria: Baseline: 3.01 ± 3.34 gm/day Last: 2.74 ± 2.4 gm/day Increased 8/28 Proteinuria (gm/day) 4,5 4,0 3,5 3,0 2,5 2,0 1,5 1,0 N = 27 Baseline 27 Last Stable 9/28 Decreased 11/28 p = 0.67
Proteinuria 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Proteinuria Proteinuria None 0-3 gm/day >3 gm/day (n = 6) (n = 11) (n = 11) Baseline 0 2.15 ± 0.63 6.86 ± 3.48 Last 2.4 ± 2.82 2.96 ± 0.95 4.73 ± 2.36 p 0.09 0.43 0.14 Increased 3 3 2 Stable 3 4 2 Decreased - 4 7
Acute Phase Response Erythrocyte sedimentation rate Baseline: 66.1 ± 31.75 mm/hour Last: 50.7 ± 35.99 mm/hour p = 0.083 C-reactive protein (CRP) Baseline: 23.55 ± 24.26 Last: 14.22 ± 17.63 p = 0.118
Responders vs Non-responders Disease duration (years) Duration of treatment (months) Baseline creatinine* Responders (n = 18) Non-responders (n = 10) 14.8 15.7 28.8 27.4 0.88 ± 0.42 1.49 ± 0.61 Baseline proteinuria 2.42 ± 3.36 3.65 ± 3.74 *p = 0.05; p = 0.406
Safety Safety was evaluated among all 32 patients Deaths (n = 6): 4 patients died with sepsis (1 of them culture proven). 3 died within 1 month of their last dose, the other patient died 3 months later. 2 had used all 3 TNFα antagonists successively. 1 patient had massive bleeding from bladder 6 months after she stopped infliximab, 1 patient died with bleeding following fondaparinux use after hip prosthesis surgery, 26 months after she stopped infliximab.
Other side effects Upper respiratory tract infection: 4 Pneumonia: 2 Urinary tract infection with vancomycin resistant enterococci: 1 Gluteal abcess: 2 Popliteal artery thrombosis: 1 Retinal vein thrombosis: 1 Internal jugular and left subclavian thrombosis: 1 Anaphylactic reaction: 2 Rash: 4 Psoriasis like eruption:1
Infliximab vs Etanercept Infliximab (n = 17) Etanercept (n = 8) Baseline Cr 1.27 ± 0.65 1.17 ± 0.64 Last Cr 1.77 ± 1.38 1.25 ± 0.87 p 0.04 0.73 Baseline proteinuria 2.48 ± 3.29 4.02 ± 4.51 Last proteinuria 1.98 ± 1.8 2.43 ± 2.05 p 0.58 0.22
Infliximab vs Etanercept Infliximab (n = 17) Etanercept (n = 8) Upper resp tract inf 4 0 Gluteal abcess 1 0 Rash 3 1 Anaphylactic reaction Popliteal artery occlusion 1 0 0 1 Died 2 (unrelated) 1 (sepsis)
CONCLUSIONS Treatment with TNFα antagonists over one year seems to stabilize proteinuria and reduce the progression of serum creatinine levels. However caution is needed due to a high number of deaths and other serious adverse events.
CONCLUSIONS Patients with higher serum creatinine levels at baseline respond less to treatment with TNFα antagonists. Randomized trials are needed to determine whether these agents really change the course of amyloidosis and whether there are differences between agents regarding efficacy and safety.
ACKNOWLEDGEMENT Huri Ozdogan Hasan Yazici Sebahattin Yurdakul Vedat Hamuryudan Izzet Fresko Melike Melikoglu Emire Seyahi Koray Tascilar Dilsen Cevirgen Mine Batumlu