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1. SYSTEMIC SCLEROSIS Dr.PRAVEEN NAGULA

2. It is much simpler to buy books than to read them and easier to read them than to absorb their contents. SIR WILLIAM OSLER

3. Background Scleroderma is derived from the greek words skleros (hard or indurated) and derma (skin). HIPPOCRATES first described this condition as thickened skin. First detailed description by Carlo Curzio in 1752. Term scleroderma --- GiovambattistaFantonetti Systemic nature of the disease by Robert H.Goetz.

4. Introduction Dr.a.g.mauriceraynaud Chronic systemic disorder of unknown etiology. Characterised by thickening of the skin (scleroderma) and distincitive involvement of multiple internal organs most notably lungs , GIT , heart ,kidneys. Skin induration limited to fingers( sclerodactyly) No skin induration (SSc sine scleroderma) RAYNAUD’S phenomenon is predominant feature seen.

6. Five weeks earlier, her hands had been swollen, erythematous, and pruritic, but these symptoms resolved without treatment.

7. The patient also described flulike symptoms during this same period of time.

8. The review of systems was significant for slight dyspnea without chest pain, heartburn, difficulty swallowing pills, bloating, and abdominal distention.

10. Definition SSc is a multisystemic ,autoimmune disease affecting small arteries,microvessels and fibroblasts resulting in vascular obliteration,collagen accumulation and scarring (fibrosis) of skin and internal organs. Leads to hidebound skin,damage of GIT,Lungs,Kidney,Heart. Serologic specificity of the disease is the presence of ANA ,directed against cellular nuclear enzymes, like DNA topoisomerase -1 (anti –Topo 1 ) and RNA polymerase,as well as centromeric proteins (anticentromereAb)

11. Diagnostic criteria The AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) criteria for the classification of systemic sclerosis. One major criteria,two or more minor criteria for diagnosis. MAJOR criterion : PROXIMAL scleroderma –characterized by SYMMETRICAL thickening,tightening and induration of the skin of the fingers and the skin proximal to the MCP /MTP joints. these changes may affect the entire extremity,face,neck,trunk. MINOR 1.SCLERODACTYLY – thickening,induration,tightening of the skin limited only to fingers. 2.DIGITAL PITTING SCARS/LOSS OF SUBSTANCE FROM THE FINGER PAD–due to ischemia. 3.BIBASILAR PULMONARY FIBROSIS-b/l reticular pattern of linear or lineonodular densities in basilar portions of the lung on CXR.diffuse mottling/honey comb lung not attributable to primary pulmonary disease

13. Affects all races.

14. Incidence is 9-19 cases/million/year.

15. Female predominance.

16. Child bearing ages.

17. African americans >whites..earlier age

18. Non mendelian pattern of inheritance.

19. Concordance among twins is low.,but ANA is high..

20. Juvenile onset systemic sclerosis is uncommon.

22. Pathology Following pathogenic mechanisms always present: Endothelial cell injury Fibroblast activation Cellular and humoral immunologic derangement. Activation of the immune system is an outstanding disease feature. –autoantibodies,perivascular lymphocytes (cd4 T ) Chronic forms of GVHD shares features of SSc.

23. pathogenesis

24. Pathogenesis

25. Clinical description The condition may be divided into different subtypes DIFFUSE CUTANEOUS SSc (DcSSc) LIMITED CUTANEOUS SSc (LcSSc ) SYSTEMIC SCLEROSIS SINE SCLERODERMA DcSSc – abrupt in onset,RP is common,thickening of trunk ,acral skin edema –earliest features,TFRs,Pfbirosis,renal crises. LcSSc – RP years before ,skin induration limited to hands,face,feet—CREST. SSSc ---visceral disease without skin involvement.

26. SUBSETS OF SYSTEMIC SCLEROSIS

27. Limited SSc/diffuseSSc

28. SYSTEMIC SCLEROSISclinical features-management Dr.PraveenNagula

30. Tip of the nose , earlobes can also be affected.

31. Triggers – exposure to cold, temperature,stress,vibration.

32.  frequency ,severity in winter.

34. PRIMARY –exaggerated physiological response to cold.

36. Positive family h/o

37. Absence of digital necrosis

38. No ulceration , gangrene

39. Negative ANA test

40. Secondary ---- > 30 yrs

41. More severe

42. Assosciated with ischemia,infarction of digits.

43. NAIL FOLD MICROSCOPY – normal with regularly spaced vascular loops – primary,distorted widened ,irregular loops,dilatedlumen,vascular dropouts.

46. Symmetrical ,B/L

47. In diffuse type – edema replaced by skin thickening..distal to proximal – centripetal fashion.

48. Skin is firm ,coarse and thickened.

49. Darkly pigmented extremities and trunk.

50. Diffuse tanning in the absence of exposure to sun –very early feature.

51. Vitiligo like hypopigmentation –in dark skinned individuals.

52. Pigment loss spares perifollicluar areas – salt and pepper appearance of skin –scalp ,upperback ,chest.

53. Obliteration of appendages of hair.

54. Loss of transverse creases on dorsum of fingers

57. Resembles of HHT .face,lip,oral cavity.

58. ATROPHY of skin – slow healing ulceration on extensor surface of PIP joints.,volar pads.

59. DIGTIAL pits – healed ischemic ulcers.

60. Resorption of terminal phalanges – acroosteolysis.

61. Calcium deposits in skin ,soft tissue.. CREST syndrome – calcium hydroxyapatite crystals.

62. Finger pads,palms,extensor surfaces.

65. Skin features Calcinosistelangiectsias

67. ILD,PAH

68. Less frequently –aspiration pneumonitis , pulmonary hemorrhage , obliterativebronchiolitis , pleural involvement , restrictive ventilatory defect due to chest wall fibrosis , spontaneous pneumothorax.

69.  broncho alveolar carcinoma

70. Asymptomatic until advanced.

71. Most frequent symptoms of pulmonary inv. Are subtle .

72. Velcro crackles at lung base.

74. 16-43% are affected.

75. NORMAL FLOW RATES.

76. At risk are MALE,AFRICAN,diffuse skin inv.,severeGERD,topoisomerase I autoAb.

77. Rapid progression in first 3 yrs of onset –32%  /year.

78. CXR,HRCT,BAL,LUNG BIOPSY.

79. HRCT more sensitive,reticular linear opacities in lower lobes,mediastinallymphadenopathy,ground glass appearance.

80. Non specific interstitial pneumonitis –better prognosis.

82. 12-25% have PAH

83. In assosciation with ILD/solitary.

84. Usually downhill course –RHF –death.

85. At risk are – Ls SSc with anticentromereantibodies,late age of onset,severe raynauds,U1 –RNP,U3 RNP fibrillarin,B23 Ab.

86. Asymptomatic,exertionaldyspnea.

87. PASP >40 mm Hg at rest in 2d echo.

88. Decreased DLCO

89. Right heart catheterisation accurate.

90. Increased BNP,Nt BNP levels

92. Asymptomatic /weight loss

93. Abn motility of intestines.

94. Prominent atrophy ,fibrosis of smooth muscle,intactmucosa,obliterative small vessel vasculopathy – all over GIT .

95. Oropharyngeal – common

96. Xerostomia

97. Oral aperture

98. Periodontal disease

99. GERD – early

100. LES pressure

101.  clearance

102. Increased emptying time.

103. Gastroparesis – early satiety

104. Distention,abd pain

105. Increased reflux

107. Subepithelial lesions

108. Diffuse small vessel vsculopathy

109. Watermelon appearance

110. Recurrent GI bleed occult

111. Fat ,protein malabsorption,vitamin b12

112. Wide mouth sacculations in the colon occur –perforation.

113. Pneumatosiscystoidesintestinalis

114. Primary biliary cirrhosis may coexist.

116. SCLERODERMA renal CRISIS –dreadful complication of SSc.

117. 20-25% pts

118. < 4 yrs of onset of diseases

119. Survival <10 % until ACEI

120. It is due to OBLITERATIVE VASCULOPATHY of renal cortical arteries.

121. RBF  JGA hyperplasia  renin secretion  RAAS  renal vasoconstriction malignant HTN.

122. RBF  vasospasm,dehyration,hypotension.

123. At risk -- africanamerican,male,diffuse skin involvement,ab to RNA polymerase III

124. Impending renal crises – palpable tendon friction rubs,pericardialeffusion,new unexplained anemia,thrombocytopenia.

125. Localised scleroderma –infrequent development.

127. 10% normal BP – normotensive renal crises.

128. Urinalysis -- proteinuria,microscopichematuria,fragmented RBCs

129. Rapidly progressive oliguric renal failure follows

130. D.D – TTP commonly misdiagnosed.

131. Creatnine > 3 mg/dl at presentation –poor prognosis.—permanent hemodialysis –high mortality,

133. Can occur secondary to renal ,pulmonary involvement.

134. LVDD is frequent.

135. LVDD –due to HTN ,myocardial fibrosis.

136. Asymptomatic until HF ,arryhthmias occurs.

137. Myocarditis in assosciation with inflammatroypolymyositis.

138. Conduction defects due to fibrosis of conduction system.

142. Biopsy of the minor salivaryglands –fibrosis rather than lymphocytic infitration.(sjogren’s syndrome)

143. Hypothyroidism –fibrosis of gland.

144. CNS is generally spared . Sensory trigeminal neuropathy due to fibrosis /vasculopathy can occur.

145. Pregnancy -adverse outcomes

146. Cardiopulmonary complications,new onset renal crises can occur.

148. Most common is mild normocytic /microcytic anemia –chronic inflammation

149. Serum iron is low or normal,ferritin is elevated.

150. Iron deficiency anemia –occult GI bleed (WATERMELON STOMACH),chronic esophagitis.

151. Macrocytic anemia – vitmainb12,folate,bacterial overgrowth,drugs

152. Acute microangiopathic anemia –mechanical trauma—renal crises

153. Thrombocytopenia ,leukopenia –DRUG toxicity.

154. ESR is normal

156. Highly specific are anti topoisomerase –I (Scl 70) and anti centromereAb

157. Specific ab profile remains stable over time.

158. Topoisomerase I ab 31% of dcSSc ,13% of lcSSc

159. Anticentromereab in 38% of lcSSc,2% of dcSSc.

160. U3RNP fibrillarin –characteristic nucleolarfluoroscencepattern,Th/To,PM/Scl .

161. No direct pathogenic role has been established for SSc associated autoantibodies..

165. Presence of skin induration with a characteristic symmetrical distibutionpattern,typical visceral organ manifestation-establishes the diagnosis with high certainity.

166. Full thickness biopsy – required for diagnosis of scleredema,scleromyoxedema,nephrogenic systemic fibrosis.

167. lcSSC– CREST for diagnosis

168. Nail fold microscopy for differentiation from primary raynaud’s

169. Diffuse edema of fingers..

172. 2.physical trauma –jack hammer

173. 3.chemical exposure

174. 4.drugs toxins – toxic oil syndrome,ergotamine,Bblockers ,carbidopa,5HT .

176. 2.scleroderma like skin changes

178. 2.idiopathic pulmonary fibrosis

179. 3.sarcoidosis

181. Multiple interventions are avialable in alleviating the symptoms –slowing progression of organ damage.

182. Treatment approaches to be individually tailored.

183. Optimal management – prompt,accuratediagnosis,classification,riskstratify,earlyrecogntion of organ based complicatyions,regular monitoring of progression,diseaseactivity,response to treatment,[patient education.

184. Holistic approach is needed.

185. Combination of drugs are used.

187. Glucocorticoids - stiffness and aching in pts with early stage disease.

188. Do not influence the progression of skin/internal organ involvement.

189. ↑risk of scleroderma renal crises at high doses.

190. Avoid if possible.

191. Low dose ,brief periods.

192. Cyclophosphamide –daily oral/IV in SSc related ILD.

193. Reduces the progression of ILD ,stabilises,improvement in skin induration.

194. Early stage SSc/extensive pulmonary involvement –candidate

195. Rx for 6- 12 months ,optimal duration not known.

196. Benefits  toxicities

198. Potential profibrotic effects --? Use in fibrotic phase

199. Mycophenolatemofetil– improvement in skin induration

200. Well tolerated

201. Immunomodulation– cyclosporine,azathioprine,extraxorporealphotopheresis,thalidomide,rapamycin.

202. Immune ablation with high dose chemotherapy followed by autologous peripheral stem cell reconstitution

204. Immunosuppressive activity

205. Prevents cross linkage of collagen fibres.

206. Stabilises,improves skin induration

207. Prevents new organ involvement

208. Improved survival

209. No effect in early active SSc

210. 750 mg/d

211. Minocycline

212. Recombinant relaxin

214. Minimize cold exposure.,Avoid drugs

215. Biofeedback therapy.

216. CCBs –diltiazem,nifedipine –ADVERSE effects

217. ACEI –not effective

218. ARBs –losartan well tolerated.

219. 1 blocker –prazosin

220. Sildenafil ,Fluoxetine ,Topical NTG, IV PROSTAGLANDINS.

221. Empiric treatment with statins,antioxidants

222. Low dose asprin,dipyridamole –useful

223. Digital sympathetectomy in severe cases

226. Symptomatic –oral endothelin receptor antagonist

227. Diuretics

228. Oral anticoagulants

229. Digoxin

230. Bosentan –increases exercise tolerance,decreases PAH progression.

231. 0 2 –nasal cannula

232. Sildenafil –short term benefit

233. Parenteral prostaglandin analogues –epoprostenol,teprostinil IV/sc infusion.

234. Iloprost –inhalation

236. Outcome determined by amount of renal damage

237. Avoid NSAIDs,glucocorticoids

238. Rx –ACEI ,short term dialysis.

240. D penicillamine

241. Cyclophosphamide

242. Regular skin massage

243. Telangiectasia –laser pulse dyed laser

244. Finger tip ulcerations –occlusive dressings

245. Infected ulcers –topical Abs

246. Surgical debridement

248. Early inflamatory changes subside in 2-4 yrs..organ involvement occurs here.

249. New organ involvement is rare after skin involvement reaches peak.

250. Skin regression occurs in the order of occurrence

251. Sclerodactyly ;contractures persist.

252. lcSSc better prognosis.

253. dcSSc –5 ,10 YR SURVIVAL RATES –70%,55%

255. young age of onset

256. African american race

257. Extensive skin thickening

258. Truncal involvement

259. Visceral organ involvement

260. Topoisomerase I ab

262. Scope for research

263. Unresolved questions

264. Etiology

265. Pathogenesis

267. High Dose Cyclophosphamide for Treatment of Scleroderma

268. Digital Ischemic Lesions in Scleroderma Treated With Oral TreprostinilDiethanolamine (DISTOL-1)

269. Pulmonary Involvement in Scleroderma: A Clinical Study of the Safety and Efficacy of MycophenolateMofetil in Scleroderma Patients With Lung Involvement

270. Sildenafil Effect on Digital Ulcer Healing in sClerodErma SEDUCE STUDY

271. Effect of Bosentan in Scleroderma Renal Crisis (ScS-REINBO)

272. Efficacy and Safety of Imatinib in Scleroderma (SCLEROGLIVEC)

274. RULE out other causes.

275. Anti topoisomerase –dcSSc,anticentromereab -LcSSc

276. After diagnosis risk stratify the patient.

277. Regular follow up and monitoring.

278. Patient education is needed.

279. Treatment is individualised.

280. Renal crises is an emergency.

281. ACEI are to be started in a pt with HTN.

282. No treatment for calcinosis cutis

283. Imatinib in near future….

286. sagittarian