1. MORPHOEA Presenter -Aatish Tamta Moderator-Dr Amit Tiwari Sir

2. INTRODUCTION A group of related conditions characterized by varying degrees of sclerosis, fibrosis & atrophy in the skin & subcutaneous tissues, sometimes extending deep into the muscle, bone & brain Extracutaneous manifestations occur in 25% of cases No internal organ fibrosis & vascular changes exists Antinuclear antibody positivity is common

3. CLASSIFICATION(PETERSON ET AL.) Plaque morphea – Morphea en plaque Guttate morphea Atrophoderma of pasini & pierini Lichen sclerosus Keloidal morphea Linear morphea – Linear morphea of the limbs & trunk En coup de sabre morphea Progressive hemifacial atrophy / Parry Romberg Syndrome Deep morphea - Subcutaneous morphea Morphea profunda eosinophilic fasciitis Disabling pansclerotic morphea Bullous morphea Generalised morphea

4. The classification remains controversial. It included atrophoderma of Pasini and Pierni, Lichen sclerosus and eosinophilic fasciitis. It does not include mixed subtype.

5. LAXER AND ZULIAN CIRCUMSCRIBED MORPHOEA Superficial Deep GENERALIZED MORPHOEA LINEAR MORPHOEA Trunk/limb variant Head variant PANSCLEROTIC MORPHOEA MIXED

6. KREUTER ET.AL. Limited type Morphea( plaque type) Guttate morphea Atrophoderma of pasini & pierini Generalised type Generalised localized type Disabling pansclerotic type Eosinophilic fasciitis Linear type Linear localised scleroderma En coup de sabre type Progressive hemifacial atrophy Deep type

7. MODIFIED CLASSIFICATION OF MORPHEA

8. EPIDEMIOLOGY Incidence – 4 to 27 per million per year Prevelance – 0.05% at age 18 years & 0.22% at age 80 Mc in child - Linear>Plaque> generalized> deep Mc in adult – Plaque> generalized> linear Age- 75% of plaque disease occur b/w 40 & 50 years 75% of linear disease occur b/w 2 &14 years Sex- common in women Adult pansclerotic morphea is more common in men Ethnicity- affects all races

9. Associated diseases mostly with generalized morphoea AICTDs AITD Vitiligo Diabetes mellitus Psoriasis Multiple sclerosis IBD Lichen sclerosus

10. PATHOPHYSIOLOGY Predisposing factors Genetics Trauma Radiation Infections Drugs

11. GENETICS HLA-DRB1*O4:04 and HLA-B*37 (genralised and linear morphoea) family history is more likely in generalised form. INFECTIONS Borrelia burgdorferi sensu stricto (USA) and B.afzelii (Eurasia) But no conclusive evidence. RADIATIONS Especially in case of Ca breast -1/500

12. Trauma Accidental trauma, surgery, insect bite reactions,vaccinations,injections. (more in linear and deep morphoea) Vaccination- Hep b, MMR,DPT, BCG, pneumococcal vaccine. Injectins- vit B 12, vit K Mechanical trauma - Isotopic- ie morphea at site of healed lesion seen in 6% isomorphic- ie lesions developing at site of repeated trauma in 9%

13. Drugs mechanism- development of drug specific lymphocyte response and autoantibody production causing endothelial damage and inflammation. eg-bleomycin, pentazocine,progestin, vitB 12, vit k, cocaine, D- penicillamine, paclitaxel, ibuprofen, gemcitabine, bromocriptine, bisoprolol, mitomycin C, balicatib.

14. Autoimmunity – supported by increased serum levels of B- Cell activating factor &variety of antibodies ANA positivity SS- DNA antibody Antihistone antibody – 12% cases (linear subtype), associated with more extensive disease Antifibrillin -1 antibody Antibody to MMP-1 Antitopoisomerase antibody- 3.2% pts Anticentromere antibody- 1.7% pts Antids DNA antibody -2.3 to 14% cases SPECIFIC TO SCLEROTIC SKIN DISEASE

15. Pathogenesis Three major components Vascular damage activation of T cells Altered connective tissue formation by fibroblasts. Role of miRNA Downregulation of miR-7 and miRNA-19A

16. IMMUNOPATHOLOGY INFLAMMATORY PHASE- Th1/TH17 response FIBROTIC PHASE- Th2 response Increased collagen deposition, decreased collagen degradation Pro –fibrogenic factors line IL-3, 4, 6, 10, TGF-β, CTGF, PDGF increased Vascular injury leading to increased expression of VCAM & ICAM

19. TRANSITION FROM Th1/Th17 in the early stage to Th2 in later stages

20. HISTOPATHOLOGY Early inflammatory stage- pronounced lymphocytic infiltrate present in lower dermis and subcutaneous fat Large areas replaced by newly formed collagen fibrils, swollen, parallel to skin surface Occasionally mast cells & eosinophils detected Vascular changes mild in dermis & subcutis, mainly endothelial swelling & oedema of vessel wall Sclerotic stage- inflammatory phase disappears Collagen consists of thick closely packed, hyalinized bundles with few fibroblasts Eccrine glands are atrophic & tightly bound down by the newly formed collagen

22. Clinical features Onset and progression- slow & insidious Lesions begin with bruise like appearance F/b central sclerosis associated with change in skin colour and texture to thickened, waxy, yellowish white Central sclerosis surroubded by erythematous to violaceous ‘ lilac ring ‘ reflecting disease activity

23. LIMITED TYPE LIMITED PLAQUE MORPHEA Round to oval lesions>1 cm in upto 2 out of 7 anatomical sites Plaques located mostly on trunk, can occur anywhere Breasts often involved, nipples & areola spared Histopathological changes limited to epidermis & dermis

25. GUTTATE MORPHEA Rare variant Multiple, small ( <1cm ), erythematous to yellowish white, mildly indurated lesions Most frequent on trunk Lesions are superficial, crinkled shiny surface resembling extragenital lichen sclerosus

26. ATROPHODERMA OF PASINI AND PIERNI Rare 0.1% of childhood morphea Primarily superficial and atrophic variant Symmetrical distributed truncal lesions – most common, Single lesions and zosteriform distribution can also be present Non indurated, blue grey to brown, hyperpigmented, sharply demarcated depressed patches with cliff drop border

28. KELOIDAL / NODULAR MORPHOEA Characterized by the presence of keloid like nodules in patients with previous or coexistent morphoea. clinically keloidal or nodular lesions arising from sclerodermatous skin. histological appearace typical of either keloid or morphoea is seen homogenization and thickening of collagen bundles with increase mucin

30. Limited deep morphea Aka morphea profunda Inflammation and sclerosis found in deep dermis, panniculus, fascia & muscle Diffuse, taut, bound down skin, HP Features- Deep cutaneous sclerosis, hyalinization & thickening of collagen bundles in deep dermis, in septa of subcutenous fat and fascia Solitary lesions can also be present

32. GENERALISED TYPE Involve 3 or more anatomical sites 7 to 9% of childhood morphea 13 to 52% of adult cases Extracutaneous features like myalgia, arthralgia, fatigue common

33. DISSEMINATED PLAQUE MORPHEA Multiple, often symmetrically distributed plaques of morphea plaques may occur in different stages of evolution. Can present at several anatomical sites, some of which may coalesce Develop in an isomorphic pattern Minor trauma from clothing around waistband, under breasts and groins

35. Pansclerotic morphea Rare presentation Extensive, circumferential involvement of majority of body surface areas Sparing of fingers & toes Complicated by severe contractures, chronic ulceration & development of squamous cell ca

36. Eosinophilic fascitis Usually extensive, involves deep tissues Symmetrically involves extremities(LL), but spares fingers and face Severe exercise precede onset of diasease Early stage- painful burning erythema with pitting oedema over limbs Later on –induration and fibrosis, peau d’ orange appearance, with tethering around blood vessels, producing groove sign Eosinophilic infilterate in panniculus and deep fascia Can result in severe joint contractures

37. LINEAR TYPE More common in children Sub devided into limb / trunk variant (mc) Head & neck variant Appears to follow blashko lines, suggesting genetic mosaicism

39. HEAD & NECK VARIANT MORPHOEA EN COUP DE SABRE Usually begins in childhood Involves frontoparietal area of face and scalp in paramedian distribution Follows blashko’s lines Sclerosis involves skin & subcutis first later on fascia and bone Scarring alopecia Neurological, ocular, auditory complications well recognised

40. Progressive hemifacial atrophy Aka Perry Romberg syndrome Blashkoid lesions in territory of trigeminal nerve Unilateral, progressive, primary atrophic disease of the skin, subcutaneous tissue, cartilage & bone Altered pigmentation Gradual loss of fat & muscle, atrophy of frontal, maxillary & mandibular bones Occular and neurological complications

41. TRUNK/LIMB VARIANT Linear sclerotic bands present Coexistent or preceding plaque morphea on trunk is common Dermis, subcutis, underlying muscle & bone may be involved Lesions across joints result in flexion contractures Limb length discripancies

42. LINEAR ATROPHODERMA OF MOULIN Unilateral, depressed, hyperpigmented blashkoid plaques on trunk & limbs Onset b/w 6 and 20 years of age On histology normal dermis and collagen present Depression due to atrophy of subcutenous tissue

43. Linear deep atrophic morphoea Three cases with no preceding clinical inflammation or sclerosis, involving the subcutis and deep dermis are reported. similar to progressive hemifacial atrophy.

44. EXTRACUTANEOUS MANIFESTATION OCCURS IN 20-25% CASES Neurological(31%)- headache,migraine,seizures, peripheral neuropathy. ophthalmological(8%)-episcleritis, ant uveitis, keratitis. oral-malocclusion, tonguehemiatrophy, TMJ involvement. arthritisan joint involvement vascular- raynaud’s phenomenon GI-esophagitis, GERD. Respiratory-dyspnea more likely due to severe skin immobility.

45. COURSE AND PROGNOSIS progresses over 3-5 years, then stabilizes and eventually resolves spontaneously. residual atrophy and dyspigmentation older age of initial onset, ANA positivity are potential risk for relapse 30-50% linear morphoea have osteoarticular complications. linear moephoea - SSc in 0.9- 1.3"%

46. DIFFERENTIAL DIAGNOSIS Systemic sclerosis Scleredema Scleromyxoedema Granuloma annulare Extragenital lichen sclerosus FDE Necrobiosis lipoidica PIH Actinic L.P Steroid induced atrophy lyme disease- erythema migrans.

47. Classification of severity Age at onset Extent and depth of disease Bony, joint or CNS involvement Assessment LoSCAT (localized scleroderma cutaneous assessment tool) High severity- genealized /pansclerotic morphoea, craniofacial linear morphoea, CNS involvement, limb shortening Moderate severity- limited deep morphoea or linear morphoea of trunk or limb without evidence of high morbidity Low severity- superficial circumscribed plaque morphoea

49. ASSESSMENT OF PATIENT CLINICAL ASSESSMENT INVESTIGATION Are lesions symptomatic Measure LosCAT score Are lesions extending? Photography+/-thermography+/- USG Are these extracutaneous manifestation? Skin biopsy : deep incisional ellipse Full skin examination to determine extent MRI ( Depth of extent on limbs ), CT & activity of lesions Examine for genital lichen sclerosus EEG CK & aldolase( muscle) Full blood count eosinophils,immunoglobulins TFT, ESR, CRP ANA, ENA, RF Borrelia serology

50. DISEASE ACTIVITY AND DAMAGE early and active disease is most resposive to therapy. increase in size, new lesion, erythema and or induration at advancing edge of the lesions. DEPTH OF INVOLVEMENT Superficial lesions can be treated with topical therapy whereas lesions beyond deep dermis should be treated systemically. DISEASE PROGRESSION many patients initially diagnosed with limited morphea later progress to more extensive form, so they should be followed up. SYSTEMIC INVOLVEMENT indication for systemic immunosuppression.

53. LIMITED DISSEMINATED PLAQUE PANSCLEROTIC LINEAR MORPHOEA MORPHOEA MORPHOEA MORPHOEA Active diasease New lesions, extending lesions, inflammation, sclerotic stage Ultrapotent topical steroid Tacrolimus 0.1% Imiquimod 5% Calcipotriol Calcipotriol- betamethasone Calcipotriol+ low dose UV-A PhototherapyUV A-1, NB- UVB,UVA,PUV A Topical therapy+/- phototherapy Psychological support, physiotherapy,MLD Inactive disease Autologous fat transfer, dermal fillers,surgical correction Methotrexate Child- 1mg/kg/weeks s.c, max 25mg /week* 12 months Adult -15 to 25mg/week oral /s.c* 12 to 36 months +/-Prednisolone Child- 2mg/kg/day max 60mg for 2 to 4 weeks, tapered to 50%at 8 weeks, 25% at 16 weeks, 12.5% at 24 weeks, stopped at 48 weeks Adult – 0.5 to 1 mg/kg/ day Mycophenolate mofetil titrated upto 1-1.5g Combination therapies Mtx+MMF+/-Phototherapy Or Ciclosporin+/_ combination therapy Or Abatacept NR

54. Treatment algorithm LIMITED PLAQUE MORPHEA Topical tacrolimus LINEAR MORPHEA (FACE & CROSSING JOINTS Phototherapy Change therapy to MMF Phototherapy Occluded calcipotriene Topical imiquimod Calcipotriol- betamethaso ne Methotrexate and systemic steroids NR* 8 weeks

55. GENERALISED MORPHEA WITHOUT JOINT CONTRACTURES Phototherapy ( Better side effect profile) Methotrexate & systemic steroids Change therapy to MMF NR* 8 weeks

56. EMERGING THERAPIES Imatinib tyrosine kinase inhibitor blocks c-kit, c-Abl, PDGF receptor ILOPROST prostaglandin analogue used in SSc pt for treatment of raynauds supress the secretion of CTGF TOCILIZUMAB IL-6 inhibitor blocks inflammatory and profibrptic effect of il-6. Abatacept CTLA-4 recombinant protein inbiting t cell activation.

57. THANK YOU