Scleroderma (Morphea, Systemic Sclerosis) Flashcards
Scleroderma is a rare and devastating systemic autoimmune disease characterised by __ and __.
As the name suggest: sclero (thick), derma (skin)
Almost all patients with scleroderma have (3)
Organ fibrosis, vasculopathy
Skin thickening
Raynaud’s phenomenon
Oesophageal dysmotility
Scleroderma dance
A. Inspection
1. Sclerotic skin over face, fingers
- Smooth, shiny, tight
2. Loss of facial wrinkles
3. Perioral puckering, restricted mouth opening
4. Pinched nose
5. Telangiectasia of face, arms
6. Sclerodactyly and flexion deformities
7. Dilated nailfold capillaries and gangrene
8. Raynaud’s phenomenon
9. Palpable calcinosis
- Others - oedema, livedo reticularis, morphoea, pigmentation, scarring alopecia, vitiligo
B. Look for mixed connective tissue disease
- RA, SLE, polymyositis
C. Complications
1. Interstitial lung disease
2. Pulmonary hypertension
3. Restrictive cardiomyopathy
4. Primary biliary cirrhosis
What are the organ systems involved in SSc
A. Skin
B. Musculoskeletal
1. Arthritis
2. Myositis and myopathy
3. Intra-articular calcification
4. Osteopenia
C. Gastrointestinal
1. Oesophagus dysmotility - dysphasia, GERD
2. Intestinal dysmotility - SIBO, steatorrhoea, malabsorption
3. Pneumatosis coli
4. Colonic diverticular disease
5. Bowel obstruction
6. Primary biliary cirrhosis
D. Renal
1. Malignant hypertension
2. Glomerulonephritis
3. Scleroderma renal crisis (SRC)
E. Respiratory
1. Interstitial lung disease - restrictive pattern
2. Pleural effusion
3. Atelectasis
F. Cardiovascular
1. Restrictive cardiomyopathy (myocardial fibrosis)
2. Pericarditis
3. Pericardial effusions
4. Pulmonary hypertension
5. Conduction defects
Outline the management of SSc
General
1. Patient education and counseling
2. Multidisciplinary team approach - Rheumatology, Cardiology, Respiratory, Gastrointestinal, Renal
3. PT OT - contractures, deformity
4. Analgesia for arthritis/arthralgia
Raynaud’s phenomenon
1. Smoking cessation
2. Hand warmers
3. Vasodilators - CCB, ACEi, prostacyclin analogues
4. Sympathectomy in severe cases
Gastrointestinal
1. Low residual diet, nutritional supplement
2. Antibiotics for SIBO
3. PPI and prokinetics for reflux and dysmotility
Renal
1. Aggressive management of hypertension
2. ACE inhibitor for renal crisis
Respiratory
1. Vasodilators for pulmonary hypertension
2. Anti-fibrotic for pulmonary fibrosis (D-penicillamine, interferon gamma)
Classification of scleroderma
A. Localised scleroderma - dermal fibrosis without internal organ involvement
1. Morphea - single/multiple plaques on trunk
- Linear scleroderma - bands of skin thickening on legs or arms, face (en coup de sabre)
B. Generalised scleroderma (SSc)
1. Limited cutaneous SSc (LcSSc)
- Skin thickening over neck/face, distal to elbows/knees
- Raynaud’s, GERD, telangiectasis, calcinosis, sclerodactyly
- Late involvement of organs, rarely renal crisis
- May still develop life threatening disease
- May progress with development of antibodies
> Anti-topoisomerase (anti-Scl-70): ILD
> Anti-centromere (ACA): PAH
- Diffuse scleroderma (DcSSc)
- Skin thickening proximal to elbows/knees, truncal involvement
- Abrupt, rapid and early presentation/involvement
- RNA polymerase III antibody: renal crisis - Systemic sclerosis sine scleroderma (ssSSc)
- Internal manifestation of SSc + antibody, WITHOUT skin thickening
Natural progression of centromere positive LcSSc
Longstanding Raynauds
5-10 years - sclerodactyly, GERD, telangiectasia, calcinosis, ILD
10-20 years - PAH
Natural progression of DcSSc
Within a year - skin features, CREST
(more rapid in Scl-70, RNA pol III)
1-5 years - renal crisis, severe ILD
> 5 years - PAH
What is CREST
C: Calcinosis
R: Raynaud’s phenomenon
E: Esophageal dysmotility
S: Sclerodactyly
T: Telangiectasis
-
Outdated term and mislead impression into thinking it is an exclusive category of SSc
(In fact, LcSSc and dcSSc can both have some or all of these features)
Why does scleroderma classification matter?
Different phenotypes progresses differently, coupled with specific autoantibodies and internal organ manifestation
- LcSSc + ACA: high PAH, rarely ILD/SRC
- LcSSc + anti-Scl-70: high ILD, rarely SRC
- DcSSc + RNA-pol3: high SRC
- RNA-pol3: malignancy (necessitating age appropriate screen)
ACR/EULAR Classification Criteria for SSc
- Skin thickening of bilateral fingers proximal to MCPJ
- Skin thickening of fingers - puffy fingers, whole fingers distal to MCP
- Fingertip lesions - digital tip ulcers, pitting scars
- Telangiectasia
- Abnormal nailfold capillaries
- PAH and/or ILD
- Raynaud’s phenomenon
- Scleroderma-related antibodies
Interpretation: 9 points or more - definite SSc
Challenges in classifying limited vs diffuse scleroderma
Both limited and diffuse scleroderma may manifest similar organ system involvement, but differing percentage
Both
Skin thickening
Raynaud’s phenomenon
Arthralgia
Oesophageal dysmotility
Pulmonary fibrosis
More in limited
Telangiectasia
Calcinosis
More in diffuse
Tendon friction rub
Myopathy
Congestive heart failure
Renal crisis
Epidemiology of SSc
- Women > men (4:1)
- Younger age
- African Americans, native Americans
Pathophysiology of SSc
Unknown, but postulated
Complex interaction of genetics, sex, external triggers (silica dust)
Endothelial disruption
Platelet activation
Fibroblast proliferation
Fetal microchimerism
Increased transforming growth factor (TGF-B)
Main cause of mortality in SSc
Currently:
1. ILD (35%)
2. PAH (26%)
3. Cardiomyopathy (26%) - heart failure, arrhythmias
4. Infections (33%)
5. Malignancy (31%)
Previously scleroderma renal crisis (now 4%)
Pathophysiology of skin changes in SSc
- Excessive production of collagen, accumulation of GAG and fibronectin in extracellular matrix (by fibroblasts)
- Loss of sweat glands, hair loss in areas of tight skin
- Begins on the fingers and hands in almost all SSc
(If it begins elsewhere - morphea, eosinophilic fasciitis, scleroderma mimic should be considered) - Skin disease/progression/severity does not necessarily predict internal organ involvement.
- SSc categories and antibodies predict internal organ involvement
Modified Rodnan Skin Score (mRSS)
17 areas on the body, each graded 0 to 3
Total possible score of 51
Score over 15-20 and rapid progression within 1st year indicate severe skin thickening
Most skin without therapy softens or atrophies over 3-10 years
How would you manage skin thickening in SSc?
Acute phase - itch reduction
1. Low dose prednisolone 15mg/day
2. Benzodiazepine - pruritus
3. Gabapentin or pregabalin
4. Topical emollients
5. Avoid scratching
6. Emerging - naltrexone
Therapeutics
1. Mycophenolate mofetil (MMF)
2. Methotrexate
3. Cyclophosphamide
4. IVIG 2g/kg per month
Emerging immunomodulators
1. Tocilizumab, abatacept
2. Haematopoietic stem cell transplantation (HSCT)
What is Raynaud’s phenomenon?
Self-limiting, reversible vasomotor disturbance of distal circulation (fingers, toes, ears, nose, tongue, lips) in response to cold, stress or spontaneously
Colour change: Pallor (white) -> cyanosis (blue) -> erythema (red)
Symptoms: numbness, tingling, pain
What features in combination with Raynaud’s phenomenon would suggest early SSc?
- Positive SSc-specific antibodies
- Nailfold capillary abnormalities (drop out or dilatation)
- Tendon friction rubs
- Digital oedema/puffy hands
- Digital infarct/ulceration
- Oesophageal hypomotility (dilated oesophagus)
Describe the nailfold capillary changes and progression in SSc
Early: few giant capillaries, microhaemorrhages. No loss of capillaries, preserved distribution
Active: frequent giant capillaries and microhaemorrhages, moderate loss, mild disorganisation of architecture
Late: ABSENT giant capillaries and microhaemorrhages, severe losses. Ramification due to neoangiogenesis and disorganised
Cardiopulmonary testing in SSc
- HRCT thorax
- Lung function test (ILD) and DLco (PAH)
- Echocardiogram
- 6 minute walk test (6MWT)
- ECG +/- Holter
- NT-proBNP - surrogate
Rationality: complications of ILD, PAH, cardiomyopathy and arrhythmias
What are the commonest ILD pattern in SSc?
- Non-specific interstitial pneumonia (NSIP)
- Usual interstitial pneumonia (UIP)
Which SSc are at high risk of progressive ILD?
- Positive anti-SCl-70
- dcSSc
- Isolated nucleolar staining ANA
How are cardiopulmonary testings useful in SSc evaluation
When should we treat SSc-ILD?
Prognosis of SSc-ILD
Serial lung function test - FVC, DLco quantifies ventilatory capacity and gas exchange, clues on PAH
More robust response of cyclophosphamide in progressive ILD
- Decline > 10% predicted FVC
- Decline > 15% predicted DLco
- HRCT involving > 20-50% of lung
Prognosis
FVC < 70%, 5-year survival 60-65%
HRCT > 20% involvement, 5-year survival 60%
Should a patient with SSc-ILD undergo lung biopsy?
Typically not required, studies shown no impact in prognosis if HRCT consistent with NSIP or UIP
Indicated if:
1. Atypical pattern on CT scan
2. Alternative explanation for ILD (hypersensitive pneumonitis)
Therapeutic options for SSc-ILD
(Scleroderma Lung Studies I and II, Fibrosing Alveolitis Trial)
1. Cyclophosphamide
2. MMF (safer, better tolerated)
Refractory
1. Rituximab
2. Azathioprine
3. CNI - cyclosporin, tacrolimus
4. Autologous HSCT
Novel immunomodulators
1. Pirfenidone
2. Nintedanib
Autologous stem cell transplant (HSCT) in SSc
ASTIS trial
- Improved event-free survival, reduced mortality over 6 years
- Clinical improvement in both subjective and objective outcomes at 2 years
- However, increased mortality 1st year: 10.1%
- However, increased adverse effect 1st 2 years
SCOT trial
- Event-free survival at 5 years in 79% HSCT vs 50% cyclophosphamide
- However, mortality 3-6% HSCT vs 0% in cyclophosphamide
Recommendations:
1. Consider in early dcSSc with mild-mod internal organ involvement (within 5 years onset) AND
2. Failed immunosuppression (not improving or worsening)
3. Exclude active smokers
4. Exclude cardiopulmonary involvement
Prevalence of SSc-PH
Classification of pulmonary hypertension
Prevalence of SSc-PH: 10-15%
Classification of pulmoanry hypertension
Group 1: PAH
Group 2: PH with left heart disease
Group 3: PH with chronic hypoxia (ILD)
Group 4: Chronic thromboembolism
Group 5: Unclear or multifactorial (sarcoidosis)
What are the commonest SSc-PH?
Why is it important to classify it?
Diagnostic assessment of SSc-PAH
Commonest: group 1 (PAH)
Others: group 2 (left heart) and 3 (ILD)
However, SSc-PAH therapies are approved only for group 1
Diagnosis of SSc-PAH (group 1)
1. Right heart catheterisation
- PASP > 25mmHg
- PCWP < 15mmHg
- Pulmonary vascular resistance > 3 Wood units
(left heart disease PH - PCWP > 15mmHg)
Clinical features of PAH
- Dyspnoea
- Fatigue
- Right heart failure - lower limb oedema, TR, elevated JVP, hepatomegaly, RV heave
- DLco reducing < 60%
- TTE findings of right heart failure
- Adjuncts: elevated BNP
Risk factors for SSc-PAH
- LcSSc (longstanding)
- Long duration of Raynaud’s
- ACA or isolated nucleolar pattern ANA
- Extensive telangiectasia
- DLco < 60% in absent of extensive ILD or other causes (emphysema)
- FVC/DLco ratio > 1.6
Management of PAH
- Calcium channel blockers
- Fluid restriction and diuretics, low salt diet
- Supplemental oxygen
- Controversial for warfarin (increased bleeding risk with unclear benefit in SSc)
Specific therapies
1. Prostacyclins (inhaled iloprost or PO trepostinil)
2. Endothelin receptor antagonist (bonsentan, ambrisentan, macitentan)
3. NO potentiator/PDE5i (sildenafil, tadalafil)
4. gyanylate cyclase simulator (riociguat)
AMBITION trial - ambrisentan + tadalafil shown lesser clinical deterioration than monotherapy
SSc related cardiac complications
- Conduction system disease
- Diastolic dysfunction and group 2 PHT
- Cardiomyoparhy
- Pericardial effusion
- Pericarditis
- Coronary artery disease
Scleroderma renal crisis
Commonly hypertensive acute renal failure
Less commonly normotensive renal failure
Highest risk in patients with early diffuse skin thickening and RNA polymerase III antibody
Presentation
1. Arterial hypertension (>150/90)
2. Retinopathy
- Grade 3 flame shaped haemorrhage/cotton wool exudates
- Grade 4 papilloedema
3. Rapid deterioration in renal function (within a month)
4. Pericardial effusion
Prognosis - 50% requires dialysis; 20-40% mortality (5-year)
(among them, half achieve improved renal function with ACEi)
Abnormal laboratory tests in SRC
- RP: Rapidly deteriorating renal function test
- UFEME/dipstick: proteinuria
- FBC: Consumptive thrombocytopenia, anaemia
- PBF: Microangiopathic haemolysis (schistocytes)
- Elevated renin level (x2 upper limit)
- ADAMTS13 normal or slight reduced
Mimics to SRC
- TTP/HUS
- ADAMTS13 significantly reduced - ANCA-associated glomerulonephritis
- Can occur concurrently with SSc, but not due to SRC
- No haemolysis
- Lesser degree of hypertension
- UFEME: RBC casts present
- ANCA antibody positive
- Renal biopsy - ANCA vasculitis
Risk factors for SRC
- Early diffuse scleroderma
- Tendon friction rub
- Corticosteroids or cyclosporin use
- Anti-RNA polymerase III antibody
Poor prognostic factors for SRC
- Male
- Initial creatinine > 265 umol/L
- Normotensive SRC
- Cardiac involvement - arrhythmia, myocarditis
Treatment and management of SRC
A. Hypertensive control
1. Short acting ACE inhibitor - captopril, enalapril (ARBs are not effective!)
- Target reduction 20mmHg within 24 hours
- Avoid hypotension
- Avoid use as prophylaxis - worse prognosis
- Second line: CCB, ARB
B. Renal replacement therapy
1. Dialysis
- 50% patients require dialysis in first 24 months
- ACE inhibitors continued indefinitely even in ESRF on haemodialysis
- Kidney transplant
- Delayed at least 24 months
Gastrointestinal manifestation of SSc
Upper GI tract: oesophagus dysmotility
- GERD, dysphagia, nausea
- Stricture
- Barrett’s oesophagus (10-15%)
- Gastric antral vascular ectasia (GAVE)
- Aspiration and cough
Lower GI tract
- Hypomotility, bloating, nausea
- SIBO - fluctuating constipation/diarrhoea
- Malabsorption
- Pseudo-obstruction
- Pneumatosis coli
- Loss of rectal sphincter tone - fecal incontinence
- Rectal prolapse
Pathophysiologic progression of GI involvement in SSc
- Neural dysfunction - arteriolar changes of vasa nervorum -> dysmotility
- Smooth muscle atrophy
- Smooth muscle fibrosis
Assessment of GI motility in SSc
- Manometry
- Barium oesophagogram
- Barium swallow
- CT abdomen and pelvis
- OGD and colonoscopy
Management of oesophageal dysmotility
As per GERD
Non-pharmacological
1. Head elevation
2. Fixed mealtime, away from bedtime
Pharmacological
1. Prokinetics: metoclopramide, erythromycin, domperidone (only in early stages - late stage fibrosis renders ineffectiveness)
2. Acid reduction - antacids, H2 antagonist, PPI
3. Refractory: octreotide, botox injection
4. Surgical fundoplication
Management of SIBO in SSc
- Choice of antibiotics
- Rifaximin 550mg TDS
- Ciprofloxacin 500mg BD
- Augmentin 625mg BD
- Metronidazole 400mg TDS - Avoid loperamide
- Vitamins, minerals supplement, FODMAP
- Sacral nerve stimulation for fecal incontinence
Calcinosis is __ of calcium phosphate over the __, __ and __. (can also occur anywhere on the body)
Deposits are firm, irregular and non-tender, size __. They can be __, __ or __with __ discharge.
Cutaneous deposition
Hands (PIPJ, fingertips), periarticular tissues, bony prominences (elbows, knee extensors)
Size of 1mm to several cm
Inflamed, infected, ulcerated, chalky white material discharge
Management of calcinosis is difficult.
Medical treatment (6) and surgical (1)
Mostly unsuccessful with little supporting data, and tends to recur
Medical
1. Warfarin - inhibits vitamin K dependent Gla matrix protein
2. Aluminum hydroxide
3. Diltiazem
4. Probenecid
5. Sodium thiosulfate
6. IV biphosphonates - binds to calcium salt
Surgical
1. Surgical resection
Telangiectasia are ____ that disappears and recurs with time. They are usually harmless, only cosmetic problem
SSc telangiectasia are __, shape __, size __, found on __, __, __ and __
More common in __
Treatment with __, but will recur.
If telangiectasia occurs in GI mucosa, it is called __ (__), which can bleed and lead to IDA
Dilated vessels (arterioles, venules, capillaries)
Matte, shaped oval or polygonal macules, size 2-7mm in diameter
Found on hands, face, lips, oral mucosa
More common in limited SSc
Treatment: laser therapy - will recur
Watermelon stomach (GAVE)
GAVE (watermelon stomach)
Extensive and prominent telangiectasia of gastric mucosal surface
Resulting in acute GI bleeding, chronic IDA
Treatment: laser or argon plasma coagulation
Bone and articular involvement in SSc demonstrated by __ (__ and __)
Resorption of __, __, ___, __, __.
Presents as __ and __, rarely as __
Hand deformities and ankylosis can be due to ____ or ____
Tendon sheaths become __ and __ mimicking __
Fibrin deposition in __ and increased thickness of __ causing tendon friction rubs.
Tendon friction rubs palpated over __, __, __
More common in __
Resorption of bone (acrosclerosis, osteolysis)
Arthralgia, morning stiffness, rarely as erosive arthritis
Skin thickening tethering effect or joint involvement
Tendon sheaths inflamed, fibrinous, mimicking arthritis
Fibrin deposition in tenosynovial sheath
Increased thickeness of tendon retinacula
Tendon friction rubs occur over wrists, ankles, knees
More common in diffuse SSc (50-65%)
Muscle abnormalities in SSc
- Proximal weakness (benign myopathy)
- Type 2 muscle fibre atrophy due to inactivity and corticosteroid use
- No CK elevation - Wax and wane
- Interstitial fibrosis and fibre atrophy, minimal inflammatory cells
- Mild CK elevation
- Do not treat with steroids - Inflammatory polymyositis
- Elevated muscle enzymes
- Treated with IST
