Division of Rheumatology Systemic sclerosis MGR 리뷰를 시작하겠습. Division of Rheumatology 김 지 연

* Interstitial lung disease in connective tissue disease 목 차 * Systemic sclerosis * Raynaud’s phenomenon * Interstitial lung disease in connective tissue disease 먼저 Systemic sclerosis에 대해서 간단히 살펴보면서, 우리가 임상에서 어떤 환자에서 scleroderma를 생각할 수 있는지를 피부병변을 중심으로 살펴보고 Raynaud’s phenomenon, connective tissue disease에서 Interstitial lung disease 순서로 살펴보겠습

Scleroderma Greek word “Skleros” (hard skin) Definite scleroderma scleroderma skin changes proximal to the MCP joint or MTP joints OR two of the following 1.sclerodactyly 2. digital pitting scars or loss of finger pad 3. bibasilar pulmonary fibrosis Two forms Localized: skin and subcutaneous: morphea, linear scleroderma Systemic: systemic sclerosis: skin and internal organs Limited cutaneous scleroderma (LcSSc) Diffuse cutaneous scleroderma (DcSSc) Scleroderma는 그리스어로 하드 스킨을 뜻하는 스클레로스에서 유래된 말로, Scleroderma는 MCP joint 또는 MTP joints의 프록시말 부위의 scleroderma skin change 또는 sclerodactyly, digital pitting scars 또는 finger pad의 loss, bibasilar pulmonary fibrosis의 3개중 2개이상을 만족하게 됩니다. Scleroderma는 크게 2개의 폼으로 나누어 지는데, Localized form은 internal 올간의 침범 없이 스킨에 국한된 형태를 말하며, systemic form은 스킨과 인터널 올간을 침범하는 형태로 Limited cutaneous scleroderma와 Diffuse cutaneous scleroderma로 나누어집

Subsets of Systemic Sclerosis Limited Cutaneous SSc Diffuse Cutaneous SSc 앞서 말씀드린 대로 systemic sclerosis는 Limited cutaneous와 Diffuse cutaneous로 나누어지고 이 2개를 비교한 테이블입. Limited 타입은 skin에서 elbow 아래와 얼굴에 국한되어 침범하고 diffuse type은 얼굴, 사지, 몸통까지 침범하게 됩니다. 리미티드타입은 레이노 피노미넌가 스킨 인벌브보다 선행하지만 디퓨즈타입은 동시에 인벌브하는 특징이 있습. 풀모너리 fibrosis도 디퓨즈에서 좀더 빈번하게 일어나고 있. 오토안티바디도 Limited 타입에서는 주로 안티센트로미어가 양성인 반면, 디퓨즈타입에서는 주로 안티토포아이소메라제가 양성소견을 보이고 있습

3. Fibroblast Activation Pathogenesis 4. Visceral Fibrosis 3. Fibroblast Activation 2. Immune Response 1. Vasculopathy systemic sclerosis의 패소제네시스를 살펴보면 어떤 원인에 의해 endothelial injury가 발생하여 Vasculopathy에 의해 Immune Response가 일어나면서 Fibroblast가 Activation되고 이것으로 Visceral Fibrosis가 일어나게 됩

Pathogenesis 좀더 자세히 보시면 프리라디컬이나 하이포퍼퓨젼에 의해 endothelial cell이 damage를 입게 되고 이에 의해 Immune Response가 일어나면서 Fibroblast가 Activation되면서 콜라겐 합성이 증가하게 됩

Lesions in Different Stages of Scleroderma. 이러한 microvascular injury는 콜라겐과 스므스 셀을 증식시키고 fibrosis되어 스킨과 인터널 올건의 구조에 변형을 가져오게 됩 one of the early events in the pathogenesis of scleroderma and is characterized by endothelial-cell damage, the proliferation of basal-lamina layers, occasional entrapment of peripheral-blood mononuclear cells in the vessel wall, and initial perivascular mononuclear-cell infiltrates As shown in Panel A, microvascular injury is one of the early events in the pathogenesis of scleroderma and is characterized by endothelial-cell damage, the proliferation of basal-lamina layers, occasional entrapment of peripheral-blood mononuclear cells in the vessel wall, and initial perivascular mononuclear-cell infiltrates. Endothelial cells show signs of increased programmed cell death. One or more reactive oxygen species (ROS)–generating triggering agents could be responsible for this stage. ROS may be generated inside the vascular lumen by peripheral-blood cells47,78 or within the vessel wall by macrophages, endothelial cells, vascular smooth-muscle cells, or adventitial fibroblasts in response to one or more noxious agents. Although low levels of ROS are necessary for normal vascular function, excessive production is responsible for functional and structural damage. As shown in Panel B, uncontrolled production of ROS activates local mesenchymal cells, inducing chemotaxis, proliferation, extracellular-matrix production, and the release of cytokines and growth factors that amplify the inflammatory focus.90 An autocrine circuitry (Ha-Ras–extracellular-signal–regulated kinases 1 and 2 [ERK1/2]/ROS) maintains ROS at levels that are high because of the reduced turnover of cytokine receptors. Structural and functional abnormalities of vessel walls and intravascular changes occur, leading to overt clinical symptoms. As shown in Panel C, the next stage is dominated by fibrosis, derangement of visceral-organ architecture, rarefaction of blood vessels, and consequently, hypoxia,91 which contributes to the maintenance of fibrosis. As shown in Panel D, once the single or multiple mechanisms responsible for mesenchymal-cell activation subside or recede or mesenchymal cells themselves undergo senescence or apoptosis,81 the disease burns out. The clinical picture is dominated by internal-organ derangement. Triggering, amplifying, and maintenance factors are not necessarily confined to a single stage. Environmental, local, and genetic factors can influence the disease progression. In the inset, coupling of the NADPH oxidase to the glutathione (GSH) cycle is shown. Glucose metabolism, in particular G6PD, generates NADPH/ H+, which is rapidly oxidized by NADPH oxidase enzymes to NADP+ H+-e-. H+ enters the GSH cycle: oxidized GSH (GSSG) is reduced by GSH reductase (GRH) to GSH, which is oxidized back to GSSG by GSH peroxidase. This enzyme uses as a preferred substrate H2O2 (2GSH + H2O2 → GS–SG + 2H2O), produced by SOD and superoxide generated by the NADPH oxidase cycle. GSH is synthesized from amino acids by the enzyme γ-glutamyl- cysteine synthetase, a rate-limiting reaction, which is tightly dependent on ATP. ATP depletion reduces GSH synthesis, increases peroxides, and unleashes the NADPH oxidase cycle, which generates a large excess of ROS, unbuffered by GSH. Lesions in Different Stages of Scleroderma. Review Article : Scleroderma NEJM, 360;19, May 7, 2009

Clinical Manifestations Raynaud’s Phenomenon skin lung GI Tract kidney heart SS의 임상양상은 스킨 뿐만 아니라 렁, GI 트랙, 키드니, 하트처럼 multiorgan에서 나타나게 됩

Sclerodactyly Raynaud’s Phenomenon 그렇다면 우리가 임상에서 어떤 환자에서 scleroderma를 생각할 수 있는지를 피부 병변을 통해 살펴보겠. 이 사진은 scleroderma 환자에서 흔히 나타나는 Raynaud’s phenomenon을 나타내는 손가락으로, 손가락 끝에 well-demarcated되어 있는 팰러 소견 관찰되고 있. 또한 skin induration과 PIP 조인트에 fixed flexion contractures를 보이는 Sclerodactyly 소견 관찰할 수 있. 손의 피부는 경화된 소견을 보이고 proximal interphalangeal joints 굴곡된 채 구축되어 있다. 역시 Harrison의 환자 예제 사진과 거의 동일한 모습을 보이고 있다. Sclerodactyly. Note skin induration and fixed flexion contractures at the proximal interphalangeal joints Fig. 132.7A Nailfold capillaroscopy using a widefield microscope demonstrating (a) normal nailfold capillaries (b) “slow” phase capillaries most commonly seen in limited cutaneous systemic sclerosis characterized by capillary dilatation and (c) “active” phase nailfold capillaries typical of diffuse cutaneous scleroderma with capillary dilatation and avascular areas. Sclerodactyly Raynaud’s Phenomenon

Digital pits Digital gangrene 또한 SS 환자에서는 손가락 끝에 패인 자국들이나 디지털 갠글린과 같은 소견도 흔히 관찰할 수 있 Digital pits on the fingertip of a patient with scleroderma. Fig. 132.5 Digital gangrene on the fingertips of a patient with scleroderma. Digital pits Digital gangrene

facial features in scleroderma 다음과 같이 입 주위에 수직으로 선을 보이는 깊은 주름이 관찰될 수도 있. Facial features in scleroderma. the vertical lines or furrowing around the mouth in this patient with diffuse scleroderma. facial features in scleroderma

다음 hand x-ray에서는 앞서 case에서 보셨듯이 long-standing limited cutaneous SS 환자에서 fingertip의 resorption으로 Acro-osteolysis소견을 보여주고 있 dissolution of terminal phalanges in a patient with long-standing limited cutaneous SSc Ischemia로 resorption of fingertip으로 나타나는 소견입 Acro-osteolysis

* Raynaud’s phenomenon

Raynaud’s phenomenon Cold or emotional stress induced color changes (white or blue) of the skin of the digits of the hands or feet Raynaud’s phenomenon이란 Cold or emotional stress 에 의해 유발된 손가락 끝이나 발가락 끝의 피부 변화를 말합 color changes (white or blue) of the skin of the digits of the hands or feet

Pathophysiology of Raynaud’s Raynaud’s phenomenon의 패소피지올로지는 처음에는 손가락의 블러드를 서플라이하는 혈관의 컨스트릭션으로 하얗게 팰러한 양상을 보이다가 손가락에 deoxygenated blood로 인에 사이아노시스 양상을 보이다가 vasoconstriction이 relaxation 되면서 erythema와 hyperemia 양상을 보이게 됩 White (pallor) : Spasms of arterioles with collapse of arteries supplying blood to the fingers constriction Blue (cyanosis) Fingers deoxygenated blood Red (rubor) recovery phase features reactive hyperemia, with resulting erythema Arterioles dilate and blood returns to the skin

Classification of Raynaud’s Primary Raynaud’s phenomenon No evidence of associated disease Secondary Raynaud’s phenomenon Connective Tissue Disease Medications Occupational Obstructive arterial disease Severe cold exposure (frostbite) Hematologic disease Raynaud’s phenomenon의 분류는 크게 프라이머리와 세컨더리로 나눌 수 있습니다. 프라이머리는 다른 동반된 질환이 없는 경우를 말하며 세컨더리는 Connective Tissue Disease, Medications, Occupational 와 같은다른 질환이나 인자가 동반된 경우입

Conditions associated with Raynaud’s phenomenon 세컨더리 Raynaud’s phenomenon중에서도 류마틱 디지즈 내에서 빈도를 살펴보면 스크레로더마가 95%가 가장 많이 차지하며 SLE, 더마토마이오사이티스, 폴리마이오사이티스, 쇼그렌 순의 빈도를 보이고 있

Nailfold capillary microscopy 이러한 레이노 의 evaluation 으로 Nailfold capillary microscopy를 사용하는데 정상 카필러리는 Regular distribution & diameter를 보이며 Hair-pin or U shaped loop 소견이 보이는 반면, 레이노환자에서는 Crossed하면서 Enlarged loop 이나 avascular areas 와 같은 소견이 관찰될 수 있 Tortuous & Enlarged loop Crossed & Enlarged loop Crossed & Enlarged loop avascular areas Normal capillary

* ILD in connective tissue disease connective tissue disease에서 ILD에 대해 살펴보겠습니다

Connective tissue disease Major Categories of Alveolar and Interstitial Inflammatory Lung Disease Connective tissue disease Systemic sclerosis (50~75%) MCTD (30~50%) RA (20~60%) PM/DM (10~40%) Sjogren’s syndrome(25~10%) SLE (4~70%) Interstitial Lung Disease의 카테고리에서 CTD가 9% 의 빈도를 보이고 있으며 CTD에서는 SS, MCTD, RA, PM, 쇼그렌의 순으로 빈도를 보이고 있

Clinical Manifestations Exertional dyspnea CXR : Bilateral diffuse interstitial infiltrates PFT : Restrictive pattern Increased alveolar-arterial oxygen difference Pathology : inflammation and/or fibrosis or granuloma 임상양상에서는 Exertional dyspnea, CXR : Bilateral diffuse interstitial infiltrates, PFT : Restrictive pattern, Increased alveolar-arterial oxygen difference, Pathology : inflammation and/or fibrosis or granuloma 소견을 보이고 있

히스톨로직상으로는 NSIP, UIP,BOOP, DAD등이 있으며 NSIP는 라디얼러직상 (테이블보면서 설명하기)

HRCT UIP NSIP HRCT상, UIP에서는 both lungs에 traction bronchiectasis와 subpleural honeycombing을 동반한 coarse reticular opacities소견을 보이고 있으며, NSIP에서는reticular abnormality and traction bronchiectasis을 동반한 extensive ground glass abnormality를 보이고 있습.

Collagen vascular disease에서 ILD의 라디올러직 앤 히스토패쏠로직 파인딩을 살펴보겠 24

+++ SS에서는 NSIP가 흔하며 기타 콜라겐 바스큘라디지즈에서도 NSIP가 가장 흔히 나타나고 있

ILD in Systemic sclerosis 50~75% with Pts NSIP (m/c, 76%), UIP(11%), DAD, BOOP, LIP Sx : dry cough, exertional dyspnea PFT : restrictive pattern, DLco↓ HRCT bilateral, symmetrical GGO pattern with reticular pattern, basal and sub-pleural BAL : eosinophil or neutrophil↑(> 3%): active inflammation Systemic sclerosis에서 ILD를 살펴보면 환자의 50~75%에서 동반되며 NSIP가 가장 흔하며 그다음으로 UIP, DAD, BOOP 의 빈도로 나타납. 증상은 dry cough, exertional dyspnea형태로 나타나며 PFT상 restrictive pattern과 Dlco감소 소견을 보이며 HRCT상에서는 주로 basal and sub-pleural에서 reticular pattern을 동반한 bilateral, symmetrical GGO pattern 을 보이고 있 with reticular pattern, basal and sub-pleural BAL : eosinophil or neutrophil↑(> 3%): active inflammation

ILD in Systemic sclerosis 피겨A는 SS 환자에서의 HRCT로 traction bronchiectasis와 reticular abnormality를 동반한 GGO 패턴을 보여주는 NSIP를 시사하는 소견이 관찰되고 있으며 피겨 B에서는 프리도미넌트하게 페리페랄과 베이졀에 coarse reticular opacities와 허니쿰 양상을 보여주는 UIP 소견이 관찰되고 있 UIP shows coarse reticular opacities in both lungs with associated traction bronchiectasis and subpleural honeycombing. NSIP shows extensive ground glass abnormality, with associated reticular abnormality and traction bronchiectasis. 피겨A는 SS 환자에서의 chest CT로 traction bronchiectasis와 reticular abnormality를 동반한 GGO 패턴을 보여주는 NSIP를 시사하는 소견이 관찰되고 있으며 피겨 B에서는 프리도미넌트하게 페리페랄과 베이졀에 coarse reticular opacities와 허니쿰 양상을 보여주는 UIP 소견이 관찰되고 있

Cyclophosphamide (oral or IV) appears to be the most effective Treatment Cyclophosphamide (oral or IV) appears to be the most effective Azathioprine and the mycophenylate mofetil may be used even though there are very few data in the setting of ILD in SSc The efficacy of interferons, 5-FU or chlorambucil has not been established A lung transplant may be considered in cases of severe ILD progressing despite SS에서 ILD의 치료를 살펴보겠. Cyclophosphamide (oral or IV) 가 가장 효과가 좋은 것으로 알려져 있으며Azathioprine 과 mycophenylate도 사용도 고려해 볼 수 있.인터레론이나 5-FU 또는 클로람부실의 효과는 아직 정립되지는 않은 상태입. 또한 치료에도 불구하고 프로그레션하는 ILD에 대해서는 폐이식을 고려해 볼 수 있 mofetil may be used even though there are very few data in the setting of ILD in SSc The efficacy of interferons, 5-FU or chlorambucil has not been established A lung transplant may be considered in cases of severe ILD progressing despite

→ improved within 3 weeks and managed to walk up to 500 m treated with i.v. infusion therapy of methylprednisolone at 10 mg/kg and cyclophosphamide 15 mg/kg → failed to respond to the initial six courses of therapy, and had a further five infusions → treated with rituximab 1000 mg 2 weeks apart with 100mg of methylprednisolone premedication → improved within 3 weeks and managed to walk up to 500 m 또한 최근에는 스클레로더마 어소시에이티드 ILD에서 리튝시맵의 치료가 효과적이었다는 보고도 있

리튝시맵을 투여전과 투여후의 chest CT를 비교한 이미지에서 리튝시맵 투여후 GGO 패턴이 감소한 양상을 보여주고 있 FIG. 1. HRCT showing (A) pre-retreatment with rituximab and (B) post-treatment with the second course of rituximab, demonstrating a reduction of the ground glass appearance and resolution of the air bronchograms in midzones (arrows). At this stage, the lung bases demonstrated irreversible fibrotic changes with honeycombing