Microscopic polyangiitis & MCTD Review 시작하겠습니다. 3년차 장원석입니다.

Intern Med. 2011;50(6):591-5. Epub 2011 Mar 15. 상기 환자도 드문 case로 본 저널은 2011년 게제된 논문이며 MCTD 가 MPO ANCA 인 GN 과 동반될수 있다고 보고한 논문입니다. Intern Med. 2011;50(6):591-5. Epub 2011 Mar 15.

Mixed Connective Tissue Disease The term mixed connective tissue disease(MCTD) defined in 1972 Positive anti-U1-RNP Ab The central premise of the MCTD concept is that of an overlap syndrome associated with anti-U1- RNP antibodies that embraces features of systemic lupus erythematosus, systemic sclerosis (scleroderma), and polymyositis Am J Med 1972;52:148-59. 다음은 RNP 가 양성이어서 이에 관련된 mixed connective tissue dis 에 대해 간략히 알아보겠습니다. 72년 처음 sharp 에 의해 제시 되었으며 anti-U1-RNP Ab 양성 이면서 SLE 나 systemic sclerosis 같은 질환이 중복질환을 정의 하였습니다. 6) Sharp GC, Irwin WS, Tan EM. Mixed connective tissue disease: an apparently distinct rheumatic diseases syndrome association with a specific antibody to extractable nuclear antigen. Am J Med 1972;52:148-59. 2) Mixed connective tissue disease. Venables PJ Lupus. 2006;15(3):132. Venables PJ Lupus. 2006;15(3):132.

MCTD diagnosis MCTD 의 정의는 보시는 표에 의해 정의를 할수 있으며 본 환자는 Raynoud phenomenon/anti RNP ab 이 에 동반된 pulmonary fibrosis 에 MCTD 도 진단할수 있습니다. Internal Medicine Vol. 38, No. 5 (May 1999)

1. Introduction MPA : as a necrotizing small-sized-vessel vasculitis, with little or no immune-complex deposition, that primarily affects the kidneys and lungs. antineutrophilic cytoplasmic antibody (ANCA)- associated small-vessel vasculitis and is further characterized by few or no immune deposits in the involved vessels. Rheum Feb 1994;37(2):187–92. MPA 는 small vessel 에 염증반응으로 immune complex 없이 주로 신장이나 폐에 증상이 발생하는 질환입니다. ANCA 라는 autoAb는 small vessel 에 관련된 Ab 로 알려져있습니다. [3] Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum Feb 1994;37(2):187–92.

The kidneys are the most commonly affected organ in 90% of patients. Pulmonary involvement : fleeting focal infiltrates~ massive lung hemorrhage and hemoptysis secondary to alveolar capillaritis The kidneys are the most commonly affected organ in 90% of patients. 폐를 침범하는경우 hemoptysis등 alveolar capillaritis 를 동반하며 MPA 환자중 90% 는 신장질환을 동반한다고 알려져있습니다. 2) 2 Jennette JC, Thomas DB, Falk RJ. Microscopic polyangiitis (microscopic polyarteritis). Semin Diagn Pathol 2001; 18:3-13. 5) Agard C, Mouthon L, Mahr A, Guillevin L. Microscopic polyangiitis and polyarteritis nodosa: how and when do they start? Arthritis Rheum 2003; 49:709-715.   6 )Lane SE, Watts RA, Shepstone L, Scott DG. Primary systemic vasculitis: clinical features and mortality. QJM 2005; 98:97-111. Semin Diagn Pathol 2001; 18:3-13.

In a retrospective review of 36 patients with MPA, pulmonary involvement occurred in 22% and alveolar hemorrhage in 11% Lane et al. found pulmonary involvement in 29% and hemoptysis in 17% among 24 MPA patients. Arthritis Rheum 2003; 49:709-715. 알려진 논문에 따르면 MPA 환자에서 폐를 침범하는 경우는 약 20%정도로 알려져있습니다. QJM 2005; 98:97-111.

2. Clinical symptoms pulmonary involvement of MPA Diffuse alveolar hemorrhage bronchiolitis obliterans organizing pneumonia diffuse panbronchiolitis bronchiolitis diffuse alveolar damage pleuritis Pleureal effusion Pulmonary edema Pulmonary fibrosis 이에 대한 clinical Sx 을 알아보겠습니다. 2010 review 저널을 보면 MPA 경우 table 1 처럼 증상을 보고 하였으며 신장 침범은 거의 100% 가깝게 보고 되었습니다. 폐를 침범하는 경우는 보시는 바와 같이 Diffuse alveolar hemorrhage 부터 bronchiolitis, Pulmonary fibrosis 형태로도 나타날 수 있겠습니다. Autoimmunity Reviews 9 (2010) 812–819

Rheumatol Int . 2011 Sep 7 다음 저널은 2011년 에 게제된 MPA를 진단받은 한국인을 대상으로 한 ANCA associated vascultis의 임상 양상을 보고한 표입니다. 본환자와 같이 renal / interstial lung dis 를 볼수 있습니다.

3. Outcome Although MPA has been considered a severe disease, some mild forms have been described and, overall, its prognosis has improved. Because elderly patients are more affected by MPA (mean age 61 years vs around 50 for WG, CSS and PAN), its mortality rate is higher: 27.5% vs 13% for WG and CSS. Arthritis Rheum Mar 1999;42(3):421–30. MPA는 severe dis를 생각 되나 clinicla feature 가 mild 한 경우는 종종 좋은 예후를 보이며 진단 시점이 다른 wegener’s , PolyAngitis Nodosa 경우보다 MPA 가 늦은 나이에 진단되기 때문에 다른 질환보다 motality 가 27.5%로 높게 보고 하였습니다. [4] Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum Mar 1999;42(3):421–30. [38] Guillevin L., Pagnoux C., Seror R., Mahr A., Mouthon L., Le Toumelin P., et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the FVSG cohort. Medicine (in press). [10] Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med Dec 25 2008;359(26):2790–803. Medicine (Baltimore) 2011 Jan;90(1):19-27.

4. Treatment of microscopic polyangiitis cyclophosphamide-glucocorticoid combination therapy oral cyclophosphamide was 2–3mg/kg/day 3~ 6 months. WBC >3000/microL, ANC >1500/microL. . Ann Intern Med Mar 15 1992;116(6):488–98. Arthritis Rheum May 2000;43(5): 1021–32. 치료는 cyclophosphamide 와 steroid 병합요법을 주로 사용하여 적어도 3~6개월 투여기간을 고려하며 WBC 가 3000개 및 ANC 가 1500개 이상시 cyclophophamide 투여를 할수 있습니다. [47] Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med Mar 15 1992;116(6):488–98. [48] Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nolle B, et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients. Arthritis Rheum May 2000;43(5): 1021–32. Cyclophosphamide regimen — Cyclophosphamide is given orally in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. The white blood cell count (WBC) should be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia. The WBC should remain above 3000/microL and the absolute neutrophil count above 1500/microL.

oral cyclophosphamide +glucocorticoids remission in 85 to 90 % 75 % complete remission . Most remissions occur between two and six months . Ann Intern Med. 2009;150(10):670. N Engl J Med. 2003;349(1):36. 85~90% 관해율을 보이며 75% 경우 완전관해를 보인다 . 대개 2~6개월사이에 관해가 이루어진다

5. Prognosis MPA prognosis is weak Evidence. first months after diagnosis. Fewer than 50% of deaths are related to MPA activity. MPA long-term prognosis is less severe, although relapses are frequent. End-stage renal failure is a frequent complication of MPA, and renal transplantation could be an effective therapy in these patients. Early diagnosis, early initiation of a tailored therapy according to risk factors and a longer follow-up of the patients are needed. 아직 MPA의 예후에 대한 증거는 아직 발혀지지 않았으며 motality는 대개 첫달에 결정되며 50% 미만환자 사망이 MPA의 활성화와 관련있다. 잦은 재발에도 ,long term prognosis는 나쁘지 않으며 MPA 의 주된 합병증으로 ESRD 이며 KTP가 효과적인 치료가 된다. 초기에 진단하고 치료하고 지속적 관찰이 중요하다. Evidence regarding MPA prognosis is weak. MPA mortality is mainly concentrated in the first months after diagnosis. Fewer than 50% of deaths are related to MPA activity. MPA long-term prognosis is less severe, although relapses are frequent. End-stage renal failure is a frequent complication of MPA, and renal transplantation could be an effective therapy in these patients. Early diagnosis, early initiation of a tailored therapy according to risk factors and a longer follow-up of the patients are needed. Rheumatology (Oxford). 2011 Aug;50(8):1414-23. Epub 2011 Mar 15. Rheumatology (Oxford). 2011 Aug;50(8):1414-23.

MPA & Pulmonary fibrosis PF is found as an early lesion of MPA in many cases - Chest 2003; 123: 297–301 time to the appearance of pulmonary and renal lesions in 27 cases pulmonary lesions appeared first : 10 pts (37%) the lesions developed simultaneously : 11 patients (40.7%) the renal lesions appear first : 5 pts (8.5%) Ryumachi 1995; 35: 46–58 Histological features of lung damage appeared before glomerular changes mouse model for MPO-ANCA-associated glomerulonephritis Microbiol Immunol 2006; 50: 149–157 This suggests the possibility that some kinds of lung damage precede the onset of renal lesions. MPA 와 pulmonary fibrosis 와의 관게에 대해 알아보겠습니다. Pulmonary fibrosis는 MPA에서 초기에 발견된다고 알려져있으며 MPA 의 37%는 폐침범이 먼저 일어나고 40%정도가 같이 증상을 보인다고 보고 하였습니다. 신장을 침범하기 전에 폐에 대한 hisological feature가 먼저 나타난다고 2006년 저널에서 보고 하였으며 여러 연구에 따르면 신장질환전 폐손상이 먼저 선행함을 짐작할수 있겠습니다. 본환자에서도 pul fibrosis가 있었기 때문에 추후 신장질환에 대한 가능성을 예측할수 있겠습니다.

Case study Ann Rheum Dis 2009;68:404–407 Between 1994 and 2004 retrospectively investigated 12 patients Pulmonary fibrosis and ANCA-associated vasculitis 상기 저널은 2009년에 게제된 논문으로 1994~2004 12 patients를 대상으로 ANCA가 양성이며 pul fibrosis 와 연관성에 대해 조사하였습니다.

다음 표와 같이 ANCA involve 를 알수 있었으며 Ann Rheum Dis 2009;68:404–407

다음 저널에서도 pulmonary fibrosis가 ANCA와 관련성이 있으며 titier 가 PF의 활동성과의 연관성은 없지만 예후인자로서 중요하다고 결론내렸습니다.

IPF & ANCA The prevalence of ANCA in patients with IPF has not been extensively studied. 9% in a Japanese study / 8% in Bichat hospital The possibility that a trigger, such as an infection, could superimpose ANCA production on underlying diseases, including IPF. ANCA could play a pathophysiological role in IPF by activating neutrophils, monocytes and endothelial cells which are known to express myeloperoxidase at their membrane. Interestingly, airway epithelial cells may also express myeloperoxidase and may become a target for ANCA. promote chronic lung injury and contribute to the vicious circle of lung fibrosis. ANCA 가 있는 환자에서 IPF 유병율에 대한 연구를 없으며 감염같은 trigger 를 통해 ANCA 발현가능성을 추측하고 있다. ANCA는 ipf 에서 neutrophils, monocytes를 활성화 시키고 endothelial cells 에 myeloperoxidase를 표현하게 하며 이러한 ANCA는 airway epithelial cells 가 주요타깃이 된다. 또한 chronic lung injury을 유발시켜 lung fibrosis에 기여한다고 알려져 있다.

ANCA Titers to Measure Disease Activity and Relapse The measurement of increasing MPO- and PR3-ANCA titers predict clinical relapse in patients with WG, CSS, MPA the increase of ANCA titers - a positive likelihood ratio for a future flare Patients in clinical remission but with rising titers of ANCA randomized to increased immunosuppression - lower rate of clinical relapse no increase in immunosuppression. Controversy - the use of ANCA as a sole marker of disease activity In clinical practice, rising ANCA titers must be used in conjunction with evidence of other clinical disease activity

Cytoplasmic ANCA (c-ANCA) Diffuse, granular cytoplasmic staining pattern in IF Major c-ANCA Ag : Proteinase-3, serine proteinase 90% of typical active Wegener’s granulomatosis Perinuclear ANCA (p-ANCA) Localized perinuclear or nuclear staining pattern in IF Major p-ANCA Ag : Myeloperoxidase Microscopic polyangiitis, Churg-Strauss SD, crescent GN, Good-pasture’ SD, Wegener’s granulomatosis ANCA activated neutrophils can kill endothelial cell In vasculitis, the two relevant target antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). Both PR3 and MPO are located in the azurophilic granules of neutrophils and the peroxidase-positive lysosomes of monocytes. Antibodies with target specificities for PR3 and MPO are called PR3-ANCA and MPO-ANCA, respectively.

Microscopic polyangitis Wegener’s granulomatosis Chung-Strauss Syd ANCA Microscopic polyangitis Wegener’s granulomatosis Chung-Strauss Syd C-ANCA (Ab) ->PR3(Ag) 40% 75% 10% P-ANCA(Ab) ->MPO(Ag) 50% 20% 60% Negative 5% 30% 보시는 표는 ANCA 양성 인 MPA, Wegener, chung strauss 이며 음성이라고 무조건 r/o 할 수는 없다. 대개 90% 의 환자에서 상기 질환은 ANCA 양성을 볼수 있다. MPA 70% 환자에서 ANCA 양성을 볼수 있으며 주로 MPO-ANCA 를 보인다. Approximately 90 percent of patients with active, generalized granulomatosis with polyangiitis (Wegener's), abbreviated as GPA, are ANCA-positive. There is clearly a small subset of patients with active, generalized GPA who do not have ANCA. Furthermore, in limited forms of the disease (such as subsets in which upper respiratory tract disease predominates and renal involvement is absent), up to 40 percent of patients may be ANCA-negative. Thus, the absence of ANCA does not exclude the diagnosis of GPA. In large measure, the sensitivity of PR3-ANCA for GPA is related to the extent, severity, and activity of disease at the time of sampling [13]. 13) Antineutrophil cytoplasmic antibodies.Hoffman GS,Specks U Arthritis Rheum. 1998;41(9):1521. Approximately 70 percent of patients with microscopic polyangiitis (MPA) are ANCA positive [14]. In contrast to GPA, most ANCA-positive MPA patients have MPO-ANCA, with a minority having PR3-ANCA. Because PR3-ANCA or MPO-ANCA may occur in both GPA and MPA, these diseases cannot be distinguished on the basis of ANCA specificity. Data pertaining to ANCA and MPA are also complicated by the lack of consensus concerning the definition of MPA. The distinction between GPA and MPA is important chiefly because of differential tendencies to flare. Although both diseases may flare after the achievement of remission, GPA is substantially more likely to relapse [15]. (See "Relapsing disease in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis", section on 'Risk factors'.) ANCA serologies are useful in distinguishing MPA from classic polyarteritis nodosa (PAN), a vasculitis of medium-sized muscular arteries. Whereas nearly three-fourths of patients with MPA are ANCA-positive, classic PAN is not associated with antibodies to either PR3 or MPO. (See "Clinical manifestations and diagnosis of polyarteritis nodosa".) Renal-limited vasculitis — Pauci-immune vasculitis limited 14) Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P, Amouroux J, Casassus P, Jarrousse B Arthritis Rheum. 1999;42(3):421. 15) A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, DadonienéJ, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C, European Vasculitis Study Group N Engl J Med. 2003;349(1):36. Arthritis Rheum. 1998;41(9):1521.

RPGN Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). High power light micrograph in crescentic glomerulonephritis. The hypercellular circumferential crescent (arrows) is compressing the glomerular tuft in the center of the glomerulus and closing the capillary lumens High power light micrograph showing an active hypercellular crescent containing fibrin, which has a bright red appearance (long arrow). Note that the severe inflammatory injury has led to fragmentation of the glomerular tuft (short arrow) and to creation of a rent in the capsule (double arrow). Immunofluorescence microscopy showing intense deposition (bright areas in the upper right portion of the glomerulus) of fibrin within a circumferential crescent surrounding the glomerular tuft in any form of crescentic or rapidly progressive glomerulonephritis, including that due to anti-GBM antibody disease. Electron micrograph in RPGN showing characteristic breaks in the glomerular basement membrane (GBM) (arrows). These rents allow fibrin and cellular elements to enter Bowman's space and initiate crescent formation.

Glomerular crescents (severe renal injury) : disruption in the integrity of the glomerular capillary wall, leading to macrophage, T-cell, and plasma protein infiltration Response to treatment is dependent on the proportion of cellular versus fibrous crescents. three main groups: (1) pauci-immune (scanty or absent immune deposits), generally caused by antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), (2) linear deposition of IgG on the capillary wall owing to anti– glomerular basement membrane (GBM) disease (3) immune complex glomerulonephritis with granular immune deposits Glomerular crescents 는 glomerular capillary wall이 손상됨으로 서 macrophage, T-cell, and plasma protein 이 침착되는 것을 말하며 치료 효과는 glomerular 에 cellular 와 fibroud potion 이 중요합니다. Glomerular crescents 는 세가지 그룹으로 나누며 본 발표에서 주로 논하게 될 ) pauci-immune 과 IgG linear deposition 되는 GBM dis 그룹 3번째는 immune complex 그룹이 있습니다.

Initial events The initiating event in all glomerular crescents is the development of a physical gap : GBM and capillary wall Primary :CD4+ T cells, macrophages, and fibrin as effectors of cell-mediated immunity. Secondary series : macrophages and T cells, inflammatory mediators, and plasma proteins. fibroblasts, and mediators in Bowman's capsule →periglomerular inflammation →crescent formation The initiating event in all glomerular crescents is the development of a physical gap : GBM and capillary wall Primary :CD4+ T cells, macrophages, and fibrin as effectors of cell-mediated immunity. Secondary series : macrophages and T cells, inflammatory mediators, and plasma proteins. fibroblasts, and mediators in Bowman's capsule →periglomerular inflammation →crescent formation

IL-17–producing CD4 T cells, termed Th17 cells, are implicated in autoimmunity and likely play a role in the pathogenesis of AAV. Nephrol Dial Transplant. 2010;25:2209-17. CD4 T cell에서 전사되는 iIL17 도 autoimmunity에 중요한 역할을 하는것으로 알려졌으며 AAV 환자에서 IL 17이 증가하는것을 볼수 있다.

Formation and composition Crescents : defined as the presence of two or more layers of cells in Bowman's space 1. coagulation proteins 2. Macrophages :central to the formation 3. T cells 4. Fibroblasts 5. parietal epithelial cells. 6. Podocytes, recently activates factor VII , tissue factor inhibitor↓ and tPA ↑ & PAI-1 ↓ IL-1, TNF TGF-beta Crescents : defined as the presence of two or more layers of cells in Bowman's space 2 Macrophages :central to the formation IL-1, TNF :adhesion, proliferation, recruit TGF-beta : more fibrocellular and fibrous crescents 3. T cells : antigen recognition and macrophage recruitment