Scleroderma and related diseases

Question 1

Sclerosis definition

Answer 1

excess collagen in the absence of increase in fibroblasts (eg systemic sclerosis) primarily Collagen I and III in the dermis and SC tissue

Question 2

Fibrosis definition

Answer 2

excess collagen and fibroblasts (eg nephrogenic systemic fibrosis)

Question 3

Drugs that can cause scleroderma

Answer 3

o Bleomycin, taxanes, vinyl chloride, chlorinated hydrocarbons

Question 4

What to look for on examination

Answer 4

Localised vs generalised
Asymmetric (morpheaform), sclerodermoid (symmetric, generalised)
Superficial/deep
Over joint, contractures, telangiectasis, calcinosis cutis
Colour: erythema, violaceous, hyper/hypopigmetned, ivory white
Upper extremitiy ulcer (sclerosis/scleroderma), if lower extremity may not be – need vascular studies
Involvement of hands?
Symmetric acral to proximal progression in sclerosis
Diffuse skin tightening in sclerosis
Active inflamamation vs damage

Question 5

Skin biopsy features of Morphea/sclerosis

Answer 5

o Superficial or deep inflammation: perivascular and interstitial lymphocytes, admised with plasma cells and sometimes eosinophils
o Inflammation in reticular dermis and/or the fibrous trabeculae of the SC tissues
o Thickening of collagen bundles, square biopsy
o Loss of adnexal structures

Question 6

Initial bloods

Answer 6

o FBC – look for Eo
o ESR/CRP
o ANA/RF -
o Serum EPP for eosinophilic fasciitis

Question 7

Morphea - autoantibodies

Answer 7

+ ANA in 50% (titres do not correlate with disease course/severity - except linear morphea in children)
ssDNA, antihistone, antitopoisomerase II-alpha

Question 8

Systemic sclerosis - autoantibodies

Answer 8

+ANA in 85%

anticentromere, Scl-70, RNA pol III

Question 9

2 types of systemic sclerosis

Answer 9

Diffuse and limited

Question 10

Types of morphea

Answer 10

Plaque, linear, guttate, segmental, bullous, keloidal (nodular), profunda, generalised
Circumscribed
pansclerotic
atrophoderma of pasini-pierini

Question 11

Circumscribed type
Who
Where 
Scarring?
Clinical features

Answer 11

Most common variant in adults
Trunk, often pressure areas like waist or bra line
Only active morphea will respond to tx
Superficial or deep
Can leave scarring – atrophy and dyspigmentation
Early lesions: erythema, violaceous patches and plaques, indurated borders
Late: sclerotic, hairless, dyspigmented

Question 12

Treatment of circumscribed type

Answer 12

Superficial Tx
Topical tacrolimus (2/12) 0.1% bd 
Calcipotriol + betamethoasone dipropironate – once to twice a day
Topifal imiquimod: three times per week 
Occluded calcipotriene: twice a day 
Lesion limited therapy UVA1, UVA, NBUVB
Watch and wait
Deep Tx
Lesion limited phototherapy - 90% improved with UVA1, 80% PUVA, 77% UVA, 90% bath PUVA 
Topical tacrolimus 
MTX 
Watchful waiting

Question 13

Linear variant

Answer 13

Eg en coup de sabre
Parry Romberg – hemifacial atrophy
Cns: seizures, headaches, vascular malformations, CNS vasculitis (10%)
Eye: adnexal sclerosis, uveitis other (3%)

Question 14

Linear morphea

Investigations and treatment

Answer 14

MRI baseline, EEG, eos may be elevated.
Ophthal q3-4 months for first 3 years of disease
Face or crossing joints
MTX 15mg/m2, systemic steroids 1mg/kg (8/52) or methylpred IV 10mg/kg per day for 3 days monthly for 2-3 months
Current recommendation 2 years of MTX to reduce relapse
MMF 600-1200mg/m2 bed
Phototherapy (UVA, PUVA, UVA1 (40 treatments mean dose 3700J/cm2, longer relapse if longer disease duration prior to therapy) ,NBUVB)
physio

Question 15

Linear morphea - clinical features

Answer 15

en coup de sabre
Parry Romberg – hemifacial atrophy
CNS: seizures, headaches, vascular malformations, CNS vasculitis (10%)
Eye: adnexal sclerosis, uveitis other (3%)

Question 16

Generalised morphea features

Answer 16

> 4 plaques >3cm each and /or
/= 2 anatomic areas (of 7)
Can reduce chest wall expansion
2/3 have genital LS

Question 17

Tx of generalised morphea

Answer 17

Phototherapy (no response after 8/52)
MTX and systemic steroids (8/52)
MMF

Question 18

Features of pansclerotic

Answer 18

Consider MRI to see MSK involvement

Rare

Question 19

Histo of lichen sclerosus

Answer 19

Histo: Initially: superficial dermal oedema and band like lymphocytic infilatrate. Thinned epidermis with orthohyperkeratosis and vaculoar degeneration of the basal layer. Follicular plugging Homogenised dermal collgen papillary dermis
Risk of SCC

Question 20

Tx of LS

Answer 20

Topical CS – dip ov bd until itch resolves (1-2 weeks) then once at night
Rv 6 weeks (but usually continue for 12 weeks total), then step down to advanta fatty ointment daily, then alt with HC1%, then 2x week with HC1% other days
Phototherapies: PUVA, UVA1

Question 21

Criteria for Systemic sclerosis

Answer 21

Skin thickening of fingers of both hands proximal to MCPs (9 points) – sufficient alone
Skin thickening of fingers – sclerodactylyl (tightening to distal to MCP, proximal to PIP)(4) or puffy fingers (2)
Raynauds (3)
Abnormal nail fold capillaries (2) – in ppl with raynauds = 80% of ppl with both nail fold changes AND abs at baseline developed SSc
Finger tip lesions – digital tip ulcers (2) or fingertip pitting scars (3) DDx: ischaemic, traumatic, calcinosis, +/- infection. Ix: Doppler, vascular, xray, swab, coags, vasculitic screen
Telangiectasia (2) – mat, macules (not domed – in hereditary haemorrhagic telangiectasia). More often in patients with limited disease/CREST, cheeks, lips, palms
Pulmonary HTN/and or Interstital lung disease (2) PHTN: 10% patients, counts for 26% related deaths. ILD: 50% of patients, 35% deaths

Question 22

PHTN
Survival
Tx
Antibodies

Answer 22

PHTN – associated with >10 telangiectasias
PFTs yearly, R heart cath
2 year survival 47% prior and 71% at present
Fibrosis: Likely to be treated with Cyclophosphamide, MMF
PAH with bosentan, sitaxentan, sildenaphil, iloprost, rituximab
SSc autoantibodies (Anticentromere, anti-topoisomerase (Scl-70), antiRNA pol III) (3)

Question 23

Systemic sclerosis - prognostic factors

Answer 23

male sex, black race, older age at Dx, internal organ involvement at Dx, skin fibrosis affecting the trunk, raised ESR

Question 24

Prognosis of systemic sclerosis

Answer 24

10 year survival less than 70%

Question 25

Diffuse vs limited

Answer 25

``` Limited scleroderma (distal to elbow; limited to hands +/- forearms, feet, face) 35% interstitial lung disease, 25% pulmonary hypertension Diffuse scleroderma (proximal to elbow +/- trunk). 70% interstitial lung disease, 5% pulmonary hypertension ```

Question 26

DDx of sclerodactylyl

Answer 26

``` DDx of sclerodactylyl: - Joint o Diabetic cheiroarthropathy o Joint anklyosis - With skin issues o Fibroblastic rheumatism o Pophryia o Drugs (eg hydroxyurea, bleomycin)O ```

Question 27

Prognosis of | Diffuse vs limited SS

Answer 27

Prog: Diffuse: 10 year survival 21%, 70% 5 year survival joint contractures, GI, lungs, heart and kidneys early in 1st 5 years Limited : 10 year survival 76%, 90% 5 year survival (CREST is a subtype) tend to have pulmonary hypertension and malabsorption 10-20years post dx

Question 28

Antibodies in SS

Answer 28

ANA 60-90% tire greater than 1:160 - centromere, nucleolar, speckled Scleroderma Hallmark Abs: Patients tend to have only 1 (10% neg) Centromere 30% limited , (CREST), possible increased risk of PAHTN, ischaemic digital loss. Also in sjogrens, Hashimoto, primary biliary cirrhosis. Anti-topoisomerase: (Anti-Scl70) 20%, diffuse, pulmonary fibrosis and mortality RNA pol III-10% diffuse, rapid onset cutaneous disease, contractures, hypertensive crisis (25-35%), less pulmonary fibrosis, underlying CA, myopathy and cardiac disease, GAVE (gastric antral vascular ectasia) U1-RNP: Limited > diffuse, SLE overlap, inflammatory arthritis, myositis , PAH, ILD (thrombocytopenia

Question 29

3 stages of SS

Answer 29

Oedematous: inflammation, fingers swollen Sclerotic: early collagen deposition with varied inflammation, skin thickens = sclerodactyly. Tethering of skin, anhidrosis, dry, face: mask liked, lips thin, smaller oral aperture, radial fissures around mouth, ridging/tightening of neck Atrophic: scar, skin thins (too late to tx)

Question 30

Non skin findings of SS

Answer 30

Systemic GIs most common – decreased motility Pulmonary fibrosis & htn – greatest cause of mortality (rapid onset diffuse skin disease –poor prognostic marker), associated with autoantibody profile Scl70 Ab Renal hypertensive crisis – high morbidity (can be precipitated by high dose pred >10mg) Myositis and arthritis are common

Question 31

Tx of SS (not the raynauds)

Answer 31

``` Inflammatory: MTX 15-25mg once weekly – can have pulmonary side effects but is 1st line MMF (add or switch) 2-3g daily Cyclophosphamide oral or IV AZA 2-3mg/kg/day – not If concurrent ILD IVIG2g/kg/month Sirolimus (8 cases) Tocilizumamb (2 cases) Rituxumab Imatinib: oedema 80%, serious ADR tachyarrhythmia/cardiomyopathy ``` Phototherapy – care in SSA (ro) disease UVB 290-320 – not deep enough UVA1 & PUVA (320-400nm) penetrate deeper Both PUVA and UVA1 providign benefit in SSc

Question 32

Tx of raynauds

Answer 32

ORAL nifedipine 10-20mg tds 1st line or amlodipine 2.5mg daily - Or sildenafil - Topical 2% GTN paste – all fingers if on 2 fingers, and these dilate, others will snap into vasospasm - Losartan 50mg/day - Fluoxetine 20-40mg/day for borderline low BP - Iloprost - Avoid cold, core and hand warmers, avoid caffeine, avoid nicotine - Botox Tx Digital ulcers - Calcium channel blockers or sildenafil for prevention and active ulcer - IV iloprost

Question 33

Treatment of renal problems in SS

Answer 33

ACEI

Question 34

What do you expect if hypertensive in SS

Answer 34

Renal crisis

Question 35

Primary raynauds

Answer 35

- Triggered by cold/stress - Symmetric - No tissue injury - No identifiable secondary cause - Normal nail fold capillaries - Normal ESR - Negative serologic findings eg ANA

Question 36

Secondary raynauds

Answer 36

- SEVERE pain - Necrosis - Pterygium inversum, onycholysis, dilated nail fold capillaries, elevated ANA, >30

Question 37

DDx of morphea

Answer 37

``` Sclerosis at injection sites Lipodermatosclerosis Chronic GVHD Stiff skin syndrome Carcinoma en cuirasse morpheaform sarcoidosis morpheaform BCC Radiation induced morphed ```

Question 38

DDx of scleroderma

Answer 38

``` Generalised morphea Nephrogenic systemic fibrosis Paraneoplastic eg POEMS Sclerodema scleromyxoedema Chronic GVHD Diabetic cheiroarthropathy PCT Eosinophilia myalgia syndrome (L tryptophan) Toxic oil syndrome Drugs: Bleomycin, Taxanes, Vinyl chloride Lipodermatosclerosis Eosinophilia fasciitis Genetic: Restrictive dermopathy Hutchinson-Gilford Werner Stiff skin Phenylketoniuira Winchester Ataxia-telangiectasia Huriez H syndrome ```

Question 39

Eosinophilic fasciitis

Answer 39

``` Aka Schulman syndrome Peau d’orange and groove sign (linear depression overlying veins), extremely painful on onset 30% of morphea plaques elsewhere Carpal tunnel common Joint contracture ``` Followed use of L tryptophan, rapeseed oil, extreme exertion 30%, autoimmune (thyroid), atorvastatin, hypercalcaemia. Rapid onset Eosinophilia in 60-80%, high ESR, hypergammaglobulinaemia , predominance of pathology of fascia – MRI Can be associated with myeloproliferative disorder, pancytopenia, anaemia, thrombocytopenia. Aldolase can be a marker for activity.

Question 40

Eosinophilic fasciitis histology

Answer 40

Histo: thickening of deep fascia (10-50x normal), patchy infiltrate of lymphocytes, plasma cells and often eosinophils and mast cells in the fascia and subfascial muscle. Not all bx will have eos.

Question 41

Tx of eosinophilia fasciitis

Answer 41

MRI, Bx, Haem for bone marrow. Systemic steroids –start therapy early or MTX, AZA, MMF. 2nd line: HCQ, allopurinol, colchicine.Physio Physical therapy in all. Xerosis Mx.

Question 42

Relapsing polychondritis Dx

Answer 42

1) Histo chondritis in 2 of 3 sites: - Auricular, nasal, laryngotracheal OR 2) Chondritis in 1 of the previous and 2 other features: - Ocular inflammation, audiovestibular damage and inflammatory arthritis

Question 43

Clinical features of relapsing polychondritis

Answer 43

Immunological reaction against type II collagen, also type IX, and XI. Erythema, swelling and pain of cartilaginous portion of the auricle, sparing the earlobe Days to weeks and may affect EAM Chronic inflame can lead to destruction of cartilage -90% will develop auricular involvement, presenting sign in 20% - nasal chondritis in 70%- saddle nose (Men) - involvement of resp tract/chostochondral joints 50% -Arthritis in 50-80% -ocular inflammation in 65% - aphthae and small vessel vasculitis – more likely associated with myelodysplasitc Associated with other autoimmune disorders (25-30%) and with myelodysplastic syndromes

Question 44

Mixed connective tissue

Answer 44

High titre IgG anti U1 ribonuclear protein antibodies, raynauds, swollen hands or sclerodactylyl, myositis, oesophageal dysmotility and arthritis

Question 45

Mixed connective tissue cf SLE

Answer 45

Lower incidence of renal disease cf sle, higher incidence of pulmonary disease Most serious complication si pulmonary hypertension

Question 46

RA

Answer 46

Nodules 20% Rheumatoid vasculitis 2-5%, nut autopsy up to 1/3 Bywater lesions – small vessel lcv, nailfold throboses, pupuric papules on distal digits Felty: granulocytopenia, splenomegaly, therapy resistant leg ulcers (often pretibial) Predisposed to infection and lymphomas, leukemias Ulcers Neutrophilic dermatoses

Question 47

Interstitial granulomatous dermatitis with arthritis

Answer 47

``` Erythematous plaques (often with an annular configuration) or linea3r cords (rope sign) that favour lateral trunk, axilla, buttocks, medial thighs and groin Usually occurs in women with RA, seronegative arthritis or polyarthralgias and autoimmune thyroiditis ```

Question 48

palisaded neutrophilic and granulomatous dermatitis.

Answer 48

Symmetrically distributed umbilicated papules favouring the elbows and extensor surfaces of digits in patients with disorders such as RA, SLE, wegeners. May extrude necrobiotic collagen Histo: small vessel vasculitis with prominent n and leukocytoclasis to palisading granulomas. Both stages have basophilic degenerated collagen