Crise rénale sclérodermique

Transcription

1 Crise rénale sclérodermique Luc Mouthon Pôle de Médecine Interne, Centre de référence pour les vascularites nécrosantes et la sclérodermie systémique, hôpital Cochin, Assistance publique-hôpitaux de Paris, Paris Université Paris Descartes, Inserm U1016, Institut Cochin, Paris

2 Conflits d intérêt Consultant: Actelion, CSL Behring, Cytheris, GSK, LFB Biotechnologies, Lilly, Pfizer Subventions ARMIIC Investigateur: Actelion, CSL Behring, Pfizer Soutien financier (projets de recherche): Actelion, CSL Behring, GSK, LFB Biotechnologies, Pfizer Le laboratoire Actelion m a fait don d une cravate en 2011

3 SYSTEMIC SCLEROSIS Vascular hyperreactivity Raynaud s syndrome Renal crisis Pulmonary arterial hypertension Fibrosis Skin Lung Bowell Heart Autoimmunity Antinuclear Abs Anti-Scl70 Anti-centromere Anti-ARNPol III Anti-fibroblast Abs Dorfmüller et al. Human Pathol 2007

4 Clinical classification of SSc Diffuse cutaneous SSc Skin sclerosis proximal to elbows and knees Inflammatory features prominent in 1st 3 years Anti-Scl-70 or anti-rna polymerase Increased frequency of interstitial lung disease, renal crisis, bowel & cardiac involvement Scleroderma sine Scleroderma No skin sclerosis Limited cutaneous SSc No skin sclerosis proximal to elbows and knees Anti-centromere antibody (ACA) CREST subgroup Lung fibrosis, renal crisis & cardiac involvement less common than in dcssc Overlap syndrome Features include those of lcssc or dcssc with those of other autoimmune disease(s) Poormoghim H, et al. Arthritis Rheum 2000; 43:444-51, Denton CP and Black CM, Trends Immunol 2005; 26:

5 SYSTEMIC SCLEROSIS : EVOLUTION Diffuse ILD + PAH Myositis Lung Bowell PAH Kidney Bowell Raynaud s syndrome ILD Limited cutaneous Years Skin score Visceral involvement

6 The modified Rodnan skin score (MRSS) Uninvolved Mild thickening Moderate thickening Severe thickening Face Upper arm Upper arm Abdomen Anterior chest Forearm Hand Forearm Hand Fingers Thigh Leg Fingers Thigh Leg Disease duration at peak skin score of the patients who had dcssc from the Royal Free Hospital scleroderma database. Foot Foot Nihtyanova SI, Denton CP. Rheum Dis Clin N Am 34 (2008)

7 Disease duration and skin score in dcssc Change in skin score over 3 years in the subgroups Survival in the subgroups mrss High baseline/non-improvers High baseline/improvers Low baseline/improvers Cumulative survival (%) p= Low baseline/ improvers, n = 67 High baseline/ improvers, n = 40 High baseline/ non-improvers, n = Disease duration Disease duration Shand L, et al. Arthritis Rheum 2007; 56:

8 Case report Mrs B, born in 1950 No history of surgery, no past medical history 3 children Menopausal, substitutive therapy No family history Technical agent

9 Patient history (1) Nov 2001 Bilateral carpal tunnel syndrome Jan 2002 Lower limb oedema April kg, hands and face oedema; no joint pain Albumin 34 g/l, haemogram, creatinine normal, negative proteinuria, CRP 11, AAN negative Echocardiography and lower limbs echo-doppler normal

10 Patient history (2) May 2002 Increase of oedema, generalised pain, hyperpigmentation of skin localised to the face and calves Interruption of substitutive therapy June 2002 Sclerosis localised to the face and hands, polyarthritis, myalgias, Raynaud s syndrome Weight loss (5 kg), antinuclear antibodies 1/80, capillaroscopy: vascular ectasias PFTs: Obstructive syndrome, not reversible, normal volumes, normal TLCO Chest CT scan: Scarce reticulo-micronodular lesions

11 Patient history (3) 20th June 2002 Prednisone 1 mg/kg/day 20th July 2002 Tapering of prednisone 1st August 2002 Pulse cyclophosphamide 28th August 2002 Hospitalisation Grade IV dyspnoea Hypertension 240/120, head aches, vomiting Biology: leucocytes 16,000/mm 3, neutrophils 13,500/mm 3, platelets 80,000/mm 3, haemoglobin 10.2 g/dl, creatininaemia 329 µmol/l, urea 29.8, haptoglobin 0.1 g/l, schizocytes 1%; absence of haematuria

12 You suspect the diagnosis of SSc renal crisis (SRC). Do you need to perform a renal biopsy? 1. Yes, because a kidney biopsy is necessary to make the diagnosis of SRC 2. Yes, because histopathology can give prognostic parameters in the context of SRC 3. Yes, because I am convinced that it is not SRC but rather a crescentic glomerulonephritis 4. No, because I can make sure that it is a renal crisis without a kidney biopsy 5. No, because a kidney biopsy is contraindicated in this patient

13 You suspect the diagnosis of SSc renal crisis (SRC). Do you need to perform a renal biopsy? 4. No, because I can make sure that it is a renal crisis without a kidney biopsy SRC is defined by rapidly progressive oliguric renal insufficiency with no other explanation and/or rapidly progressive arterial hypertension occurring during the course of SSc Steen VD, et al. Ann Intern Med 1990; 113:352-7.

14 Scleroderma renal crisis (SRC) occurs in 5% scleroderma patients : 10-20% of patients with diffuse SSc About 1% in limited cutaneous forms (Steen 2003). Two time periods : Scleroderma renal crisis Before ACEi : less than 10% survival at 1 year. After ACEi: 65% survival at 5 years. In a recent work from the EUSTAR group data base, it is reported to have decreased to less than 5% (Walker UA et al. Ann Rheum Dis 2007) and less than 2% in patients with limited cutaneous SSc (lcssc).

15 Scleroderma renal crisis Definition Rapidly progressive oliguric renal insufficiency with no other explanation and/or rapidly progressive hypertension occurring during the course of SSc

16 Principales manifestations cliniques et biologiques survenant au cours de la crise rénale sclérodermique Steen et col. (Steen, 2003) Walker et col. (Walker, 2003) DeMarco et col. (DeMarco, 2002) Penn et col. (Penn, 2007) Teixeira et col. (Teixeira, 2007) Nombre de patients Age Sexe, % Hommes Symptômes < 4 ans, % ScS diffuse, % Ac antitopoisomerase 1, % Ac anticentromère, % HTA, % PA syst/diast (moyenne) Péricardite, % Insuffisance cardiaque gauche, % Arythmie, % Convulsions, % Encéphalopathie hypertensive, % Hémorragie intracérébrale, % Microangiopathie thrombotique, % Plaquettes < /mm3, % Hématurie, % Protéinurie, % / (>0,25g/j) / / (<1an) 78 17, / / * 53(>0,5 g/j) Paris 20 et 21 Octobre 2005 Mouthon et al. Clin Rev Allerg Immunol ème journée française de l HTAP

17 SRC-related clinical symptoms in 50 SSc patients at the time of SRC Parameter Hypertension (blood pressure > 140 mmhg systolic and/or 90 mmhg diastolic), n (%) Blood pressure mm Hg (mean ± SD) Results 44 (88%) Systolic ± 39.9 Diastolic ± 23.6 Cardiovascular signs Left ventricular failure, n (%) 23 (46) Pericarditis, n (%) 3 (6) Arrhythmia, n (%) 9 (18) Neurological signs, n (%) 27 (54) Hypertensive encephalopathy, n (%) 17 (34) Seizure, n (%) 5 (10) Intracerebral hemorrhage, n (%) 5 (10) Oligoanuria, n (%) (n=47) 21 (44)* Teixeira L et al Ann Rheum Dis 2008

18 SRC-related laboratory findings in 50 SSc patients at the time of SRC Parameter Results Laboratory tests Mean white blood cell count/mm 3 (mean ± SD) ± 5813 Mean haemoglobin level, g/dl (mean ± SD) 9.4 ± 2.3 Mean platelet count/mm 3 (mean ± SD) ± Thrombotic microangiopathy, n (%) 23 (46) Mean serum creatinine level, µmol/l (mean ± SD) 468 ± 293 (median: 392) Mean creatinine clearance, ml/min (mean ± SD) 18.3 ± 15.3 (median: 14.3) Hematuria, n (%) (n = 31)* 13 (42) Granular casts, n (%) (n = 30)* 4 (13) Proteinuria, n (%) (n = 38)* 20 (53) *values available for the number of patients indicated. Teixeira L et al Ann Rheum Dis 2008

19 SCLERODERMA RENAL CRISIS: The French series (91 patients and 427 controls) With SRC Without SRC p Age, years ns Limited SSc 14.2% 66% 0.01 Diffuse SSc 85.7% 34% 0.01 Guillevin et al Rheumatology, in press

20 SCLERODERMA RENAL CRISIS: The French series (91 patients and 427 controls) With SRC Without SRC p Steroids 70.3% 36.5% Oral CS 56.5% 36.5% Dose (mg) 29.3 ± ± CS before SRC 53% CS: corticosteroids Guillevin et al Rheumatology, in press

21 SCLERODERMA RENAL CRISIS: The French series (91 patients and 427 controls) With SRC Without SRC p ANA 87.4% 91.8% ns Anti-Scl70 31% 30.7% ns Anti-centromere 3.4% 28.3% Anti-RNA pol % 6.7% 0.02 Guillevin et al Rheumatology, in press

22 SCLERODERMA RENAL CRISIS: The French series (91 patients and 427 controls) Outcome Oliguria 28.6% Dialysis 53.8% - Definitive 39.6% - Temporary 14.2% Deaths within 6 months: 20.9% Deaths 6 to 12 months later: 19.8% Guillevin et al Rheumatology, in press

23 SCLERODERMA RENAL CRISIS: 91 patients with and 427 without 100 Survival rate (%) patients without renal crisis 91 patients with renal crisis Time since SSc diagnosis (months) Guillevin et al Rheumatology, in press

24 SCLERODERMA RENAL CRISIS: 91 patients with and 427 without 100 Survival rate (%) patients with normal blood pressure 78 patients with high blood pressure Time since SSc diagnosis (months) Guillevin et al Rheumatology, in press

25 Renal pathology Renal biopsy is not necessary to confirm the diagnosis of SRC in classical forms. However, a number of research groups are performing systematic renal biopsy in order to better evaluate the prognosis of SRC. In atypical clinical presentation, renal biopsy is mandatory to confirm the diagnosis of SRC. In all cases, renal biopsy will be performed after control of blood pressure. In case of severe thrombocytopenia, renal biopsy can be performed through jugular vein catheterism. Mouthon et al. Clin Rev Allerg Immunol. 2009

26 Chronic injury of an interlobular artery with mucoid changes and endothelial proliferation.

27 Ischemic glomerulus with retraction of the tuft and segmental reduplication of glomerular basement membrane.

28 Interlobular artery with mucoid changes and concentric intimal fibroplasia with so-called «onion-skinning changes».

29 Arteriole with acute lesion characterized by mucoid expansion and recent thrombosis with fibrin.

30 Endothelin 1 expression in scleroderma renal crisis ET-1 in glomerular thrombosis and along glomerular basement membranes ET-1 in arteriolar thrombosis Mouthon et al. Human Pathol 2010

31 Factors predictive of renal crisis Diffuse skin involvement Rapid progression of skin thickening Disease course < 4 years Anti-RNA-polymerase III-antibodies Newly manifested anaemia Newly manifested cardiac involvement Pericardial effusion Heart insufficiency Previous high-dose CS therapy Steen VD. Am J Med 1984; 76: Steen VD. Rheum Dis Clin North Am 2003; 29:

32 Clinical and biological characteristics of 195 patients with systemic sclerosis (SSc) depending on the presence or absence of anti-rna polymerase III antibodies (ARA III). ARA were detected in 17/195 (8.7%) of our patients. Emilie et al. Scand J Rheum 2011

33 Using multivariate analysis, detection of ARA was independently associated with dcssc [odds ratio (OR) 6.9, 95% confidence interval (CI) , p = 0.01], renal insufficiency (OR 11.7, 95% CI , p = 0.006), an absence of pulmonary fibrosis (OR 0.16, , p = 0.02).

34 Factors predictive of renal crisis: Corticosteroids In a case-controlled study, in the 6 months prior to SRC onset or to the first visit, high-dose CS ( 15 mg/day prednisone) were administered significantly more frequently in SRC patients (36%) than in controls (12%) (OR 4.37) In a retrospective study of 50 patients with SRC, 30 (60%) of the patients had been exposed to CS prior to the onset of SRC The OR for developing SRC associated with intake of CS during the preceding 3- or 1-month period were 24.1 and 17.4, respectively CS play a potential role in inducing SRC It can not be concluded that CS play a causal role These data support the crucial preventive role of avoiding CS in patients at risk for SRC Paris 20 et 21 Octobre 2005 Steen VD and Medsger TA. Arthr Rheum 1998 Teixeira L, et al. Ann Rheum Dis ème journée française de l HTAP

35 Diagnostics différentiels Insuffisance rénale d origine iatrogène (D-pénicillamine) (Steen, 2005). Insuffisance rénale fonctionnelle (insuffisance cardiaque, déshydratation, HTAP, traitement diurétique) Sténose des artères rénales (insuffisance rénale aigüe et/ou une HTA, IEC). Glomérulonéphrite proliférative ANCA-positive, le plus souvent de type anti-mpo (GP, hématurie et/ou protéinurie abondante sans HTA). MAT authentique. Fibrose néphrogénique systémique (insuffisance rénale chronique préalable, rôle du gadolinium) (George, 2006). Paris 20 et 21 Octobre ème journée française de l HTAP

36 Osteomalacia revealing coeliac disease and primary biliary cirrhosis-related anconi syndrome in a patient with SSc 42-year-old woman referred in June 2006 for diffuse noninflammatory bone pains. Diffuse SSc. Creatinine 117 µmol/l (clearance 47mL/min), hepatic cytolysis and cholestasis, normal calcemia, decreased concentration of 25(OH)-vitamin D3 (7.3ng/mL, N 10-60) Features of proximal tubulopathy (Fanconi syndrome) Terrier et al. Clin Exp Rheum 2008

37 Pronostic des crises rénales sclérodermiques Steen 2003 Walker 2003 Penn 2007 Teixeira 2008 Guillevin 2011 Patients dialysés, % Temporairement, % Permanente, % Décès en dialyse, % Décès, % * (à 5 ans)

38 Changes in causes of systemic sclerosis related deaths between 1972 and 2001 Paris 20 et 21 Octobre 2005 Steen VD, Medsger T, Ann Rheum Dis 2007, Feb 28 EPub 3 ème journée française de l HTAP

39 ACEi efficacy in SRC First report of successful Rx with ACEi 1 No randomised controlled studies of benefit Comparison with historical controls suggests major therapeutic gain 2 Single centre case-control study 108 patients % 1 year survival without ACEi 76% 1 year survival with ACEi NB cohort effect Angiotensin II receptor blockade may be useful but anecdotally less effective than ACEi. Additive effect unproven. 1. Lopez-Ovejero, et al. N Engl J Med 1979; 300: Steen, et al. Ann Intern Med 1990; 113:352-7

40 Is there a role for ACEi prophylaxis? ACEi have no benefit for RP or digital ulcers - QUINS trial 1 Use of ACEi/ATII prior to SRC blockers associated with trend towards worse outcome 2,3 Pooled data analysis from two studies gives OR 2.4 ( CI) and p=0.059 Chi Squared value A prospective international cohort study is underway 5 No dialysis Dialysis and recovery Dialysis without recovery Total Pre-SRC ACEi/ATII 7 (35%) 3 (15%) 10 (50%) 20 No pre-src ACEi/ATII 20 (42%) 14 (29%) 14 (29%) 48 Total Odds ratio Odds ratio 95% CI Fishers exact test p value Slide courtesy Christopher Denton 1. Glidden, et al. Arthritis Rheum 2007; 55: Penn, et al. QJM 2007; 100: Teixeira, et al. Ann Rheum Dis 2008; 67: Penn and Denton. Curr Opin Rheum 2008;20: Hudson et al. Int J Rheumatol. Epub 2010

41 Proposed treatment of hypertension occurring during the course of systemic sclerosis. Prospective open study Addition of Bosentan to ACEi Bussone G et al. Current Rheumatol Report 2010

42 Transplantation rénale La transplantation rénale n est envisagée qu après deux ans d épuration extra-rénale Survie des greffons de 56,7% à 5 ans (USA, , 260 patients). Cinq cas de récidive de CRS sur 260 patients transplantés (1,9%) (Pham 2005). Sous estimation probable du nombre de récidives. Ces 5 patients avaient tous développé une insuffisance rénale terminale dans l année suivant le diagnostic de CRS sur le rein natif. La ciclosporine n est pas recommandée dans le traitement du rejet de greffe (risque de déclenchement de CRS) (Ruiz, 1991). Paris 20 et 21 Octobre ème journée française de l HTAP

43 Conclusions Despite the use of ACEi, SRC remains associated with significant mortality and morbidity. Corticosteroids might increase the risk of developping SRC Corticosteroids might be spared in patients at risk for SRC Increased intra-renal expression of ET-1 in SRC (like in typical SHU with microangiopathy) Clinical relevance of ET-1 blockade