Clinical Case Conference Tuesday August 25, 2015 Dana Assis, MD

Transcription

1 Clinical Case Conference Tuesday August 25, 2015 Dana Assis, MD

2 CC: LE swelling and pain for three weeks HPI: 71F hx HTN, DM (A1c 9.6), HFrEF (45%), asthma, OA, cryptogenic cirrhosis p/w bilateral lower extremity swelling and pain for three weeks. PMHx: as above, Giant cell arteritis PSHx: None All: PCN unknown Home Medications: calcium carbonate, vitamin D, folic acid, aspirin, simvastatin, Lisinopril 2.5mg, metformin 500mg twice daily, lantus 15 units qhs, esomeprazole, dexamethasone 1.5mg twice daily Social: From Ecuador, moved to US in 2001, lives with daughter and granddaughter denies toxic habits

3 Physical Exam VS Tm 102 BP 178/94 HR 101 R 18 Gen: elderly female no distress HEENT: non icteric sclera, no conjunctival injection, mmm, no mucosal ulcers CV: tachycardic S1S2 no MRG Pulm: CTA no wheeze or crackles Abd: bowel sounds normal, no distension, tender to palpation RUQ and supra pubic Ext: 3+ pitting edema extending to knees bilaterally without skin lesions

4 Laboratory Evaluation Admit Na 132 K 4.4 Cl 99 CO2 22 BUN 39 Cr 1.3 (baseline ) Hb 8.8 (10-12) MCV 73.6 WBC 16.3 Plt 318 C3 94 (90-180) C4 11 (10-40) DNA Ab DS <12 ESR 71 CRP 90 ANA 1:80 Up/Ucr 401/118 = 3.39 LFT ast/alt 34/42 alkp 243 Tb 0.5 Db 0.2 To 5.2 Alb 2.9 5d repeat Na 137 K 4.1 Cl 106 CO2 24 BUN 34 Cr 1.3

5 Urinalysis UGlu Bili Ketone s Sp gravity Blood Protein WBC RBC Month PTA 250mg/ dl Small Large mg/ dl Admit 250mg/ dl Negativ e Negativ e Large 3+ >300mg /dl packed 5d hosp stay Negativ e Negativ e Negativ e Large 3+ blood 100mg/ dl Active sediment numerous red blood cells, white cells, no red cell casts

6 U/S renal echogenicity is within slightly increased. Right kidney 10.7cm and left kidney 11.5cm no hydropnephrosis or shadowing calculus. No solid lesion or perinephric abnormality is identified. Gross patency of the main renal artery is demonstrated on color and spectral Doppler with normal rapid arterial upstroke. Patency of the main renal vein is also demonstrated bilaterally. Non occlusive thrombus arterial, venous is not excluded.

7 Differential ANCA associated vasculitis (AAV) IgA nephropathy Anti GBM IgA vasculitis (HSP) Amyloidosis Light chain deposition disease SLE

8 AAV Granulomatosis with polyangiitis (Wegeners), Microscopic polyangitis, Eosinophilic granulomatosis with polyangiitis (Churg- Strauss) Patient Proteinase-3 Ab 70.6 and Myeloperoxidase Ab <1 GBM Ab <0.2 Dx Granulomatosis with polyangiitis, PR3- ANCA

9 Chapel Hill Criteria Revised Hill% pdf

10 Biopsy

11 Biopsy

12 Biopsy

13 Outline: Current Treatments Induction Therapy CYCLOPS RAVE Role of Plasmapheresis

14 Immunofluoresence

15 Csernok, E. & Moosig, F. Nat. Rev. Rheumatol. 10, (2014); published online 3 June 2014; doi: /nrrheum adid=74&subid=101&pageid=105

16 Pathogenesis of AAV Jennette, J. C. & Falk, R. J. Nat. Rev. Rheumatol. 10, (2014); published online 8 July 2014; doi: /nrrheum

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18 Design RCT 42 centers 12 European countries 149 newly diagnosed generalized ANCA associated vasculitis with renal involvement but not immediate life threatening disease Intervention group: PC 15mg/kg every 2-3 weeks (76 patients) or DC 2mg/kg (73 patients) plus prednisolone both groups Primary outcome time to remission Secondary outcomes change in renal function, AE, cumulative dose cyclophosphamide, death

19 Schönermarck, U. et al. Nat. Rev. Nephrol. 10, (2014); published online 5 November 2013; doi: /nrneph

20 Criteria Inclusion Criteria: A new diagnosis of WG, MP or renal-limited vasculitis (RLV) (appendix 5). Patients not previously treated with cytotoxic drugs will be permitted. Renal involvement attributable to active WG, MP or RLV with at least one of the following: elevated serum creatinine between 150 and 500 umol/l. biopsy demonstrating necrotizing glomerulonephritis. red cell casts. haematuria with >30 red blood cells/high powered field and proteinuria > 1g/24hr. ANCA positivity or confirmatory histology or both (appendix 5). ANCA positivity requires a typical CANCA pattern by indirect immunofluorescence (IIF), (preferably confirmed by anti-pr3 ELISA), or the presence of PR3-ANCA or MPO- ANCA determined by ELISA, PANCA requires confirmation by anti-mpo ELISA [6]. (Central review of ANCA serology and histology will be performed). Age years. Exclusion Criteria: More than two weeks treatment with cyclophosphamide (CYC) or other cytotoxic drug within previous year or with oral corticosteroids (OCS) for more than 4 weeks. If the patient has received >1.0g of methyl-prednisolone prior to the study start, discuss with trial co-ordinator. Co-existence of another multisystem autoimmune disease, e.g. SLE. Hepatitis Be antigen positive or Hepatitis C antibody positive. Known HIV positivity (HIV testing will not be a requirement for this trial). Serum creatinine > 500umol/l (consider MEPEX trial). Immediately life-threatening organ manifestations (e.g. lung haemorrhage or dialysis dependence). Previous malignancy (usually exclude unless agreed with trial co-ordinator). Pregnancy or inadequate contraception if female. Anti-GBM antibody positivity.

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22 hazard ratio, [95% CI, 0.78 to 1.55] P 0.59

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28 Limitations of study: not powered to detect difference in relapse rates between two groups Duration follow up was limited

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30 Figure 1 HR % CI p0.92

31 Figure 2 HR % CI p 0.029

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33 Immunosuppression up to 18months then left to discretion of investigator Exclude 14 patients did not return questionnaires No difference in AE between two limbs

34 NEJM 2010; 363:221-32

35 MOA Rituximab Nature Clinical Practice Rheumatology (2007) 3, Doi: /ncprheum0424

36 Study design Primary endpoint: remission of disease without use of prednisone at 6 months Multicenter RCT double blind double dummy, non inferiority trial Groups: Rituximab 375mg per square meter of BSA per week for 4 weeks or Cyclophosphamide 2mg/kg/day 9 US centers enrolled 197 patients

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44 N Engl J Med 2013;369: DOI: /NEJMoa

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49 J Am Soc Nephrol 18: , doi: /ASN

50 Study design Primary endpoint renal recovery defined as dialysis independence at 3 months Looking to see whether addition of plasma exchange was more effective than IV methylprednisolone Patients serum Cr > 5.8 mg/dl, new diagnosis of ANCA-associated systemic vasculitis (confirmed by renal biopsy) Secondary endpoints: renal and patient survival at 1 yr, severe AE rates

51 Screened 151 patients, randomized 137

52 Patient characteristics

53 Results serum creatinine at 12 month for those who recovered renal function between the two groups 2.24 mg/dl v 2.25 mg/dl P = 0.87

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58 PEXIVAS Trial Study Design: multi center international open label RCT in severe AAV Patients GFR <50ml/min and or alveolar hemorrhage Randomize 700 patients 1:1 to receive adjunctive plasma exchange (PLEX) in addition to standard immunosuppresssive therapy and steroids or standard immunosuppressive therapy and steroids without PLEX

59 Looking Forward: Treatment - GPA and MPA should be studied separately in future trials - Different type of organ or disease manifestation - Define Predictors of mortality : severe renal insufficiency advanced age low Hb levels high disease activity levels and cumulative organ damage - Patients at risk for relapse PR3-ANCA positive or diagnosis of GPA have higher risk of relapse than those with MPO-ANCA or MPA dx - Serial ANCA testing for prediction of relapse - Meta analysis rise in ANCA titer during remission is associated with increase risk of subsequent relapse (positive LR % CI )

60 Patient Clinical Course Treated IV methylprednisolone x3 doses, prednisone 60mg, cyclophosphamide dose 2mg/kg/day Bactrim Labs: Urine protein 175/ Urine Cr 65 = 2.69 ESR 18 CRP 1.5 Cr 1.2

61 Questions