Rheumatology SC063: Fingers Turn White And Blue: Scleroderma And MCTD, Raynaud’s Disease, Other Rheumatic Diseases Flashcards
Case 1:
- Mrs. S Ho
- F/40
- Housewife
- Previously well
- 6 month history of “cold fingers”, particularly during winter months
- On exposure to cold / change from high to low temperature / psychological stress, fingers turned white —> blue —> red (***Triphasic discolouration)
- Feel tired easily
- Weight loss 2 kg over 3 months
- “Swollen” sensation of both hands
- Intermittent arthralgia
- Progressive SOB on exertion
Joint pain, Constitutional symptoms:
- Common in multi-system autoimmune rheumatic conditions (aka Connective tissue disease)
Joint pain:
- Common
- Bilateral symmetrical proximal arthritis
- vs RA: significant swelling in synovial joints
- No significant synovial swelling, only swollen sensation
Investigations:
- CXR: Bilateral lower zone haziness with reticular shadows —> suggestive of ILD
- Hb: 10.9 (normochromic normocytic —> suggestive of Anaemia of chronic disease
- ESR: 56 (↑)
- SGOT (AST) 340 (↑), CPK 980 (↑), LDH 896 (↑) —> Muscle enzymes
- EMG: Inflammatory myopathy
- ANA 1/1080 (+ve)
- Anti-RNP +ve
Further investigations:
- Lung function test
—> ↓ VC, TLC
—> ↑ FEV1/VC and RV/TLC
—> ↓ DLCO
—> Restrictive pattern
- HRCT thorax: Early fibrosing alveolitis
Dx:
- Mixed Connective Tissue Disorder (MCTD) complicated by:
—> Raynaud’s phenomenon
—> Sclerodermatous skin changes
—> Fibrosing alveolitis
—> Low grade myositis
Connective Tissue Disorders
**Multi-system **autoimmune rheumatic conditions
Salient features:
- Young / Middle-aged **female
- **Subcaute onset
- ***Progressive course
- Cold-induced vasospasm
- Mutisystem involvement
Commonly early features:
Clinical features:
- **Unexplained fever
- **Polyarthritis
- **Photosensitive rashes
- Raynaud’s
- Nail fold changes
- Lower limb petechiae
- Alopecia
- Sicca symptoms
- Recurrent oral ulcers
- **Serositis
Laboratory:
- **Cytopenia (∵ AutoAb)
- **High ESR
- **+ve ANA
- **Hyperglobulinaemia
- ***Reversed AG ratio (↓ Albumin, ↑ Globulin)
- Urine sediments and protein (∵ small blood vessels affected —> Glomerular disease)
***Spectrum of CTD
Multi-system involvement
Classification based on Fibrosis / Inflammation
1. Fibrosis predominant (Excessive healing processes):
***Systemic sclerosis
- Raynaud’s phenomenon
- Severe scleroderma
- Internal organ involvement
- Anti-Scl70, Anti-centromere
- Inflammation predominant (Excessive hyperinflammatory immune reactions):
***SLE
- Inflammatory rashes
- Inflammatory arthritis
- Immune complex disease
- Multi-system involvement
- Multi-AutoAb - In-between:
***MCTD / Undifferentiated CTD (uCTD)
- Raynaud’s
- Scleroderma
- Inflammatory rashes
- Inflammatory myositis
- Esophageal involvement
- Lung involvement
- Anti-RNP
Classification based on Focal / Systemic inflammatory responses:
1. Focal inflammatory responses
- RA
- PBC
- Systemic inflammatory responses
- SLE - In-between
- Sjogren’s
- MCTD / uCTD
- Polymyositis (Pm)
- Dermatomyositis (Dm)
***NB: Important to note that it is a spectrum —> RA can still present with systemic inflammatory responses e.g. cutaneous manifestations, respiratory complications
Raynaud’s phenomenon vs Acrocyanosis
Raynaud’s phenomenon:
- Complete blanching of digits —> ∵ Arterial vasospasm
- ***Episodic
- Primary / Secondary
Acrocyanosis:
- Venospasm —> Stasis of venous blood in hand
- ***Persistent (e.g. hypoxaemia) / Episodic (e.g. Raynaud’s)
- No blanching
- Primary / Secondary
NB: In Rheumatology, approach to both is same
Primary vs Secondary Raynaud’s phenomenon
Primary / Idiopathic (generally related to ambient temperature, more seen in cold countries)
Secondary:
- **CTD including vasculitis (MUST consider)
- **Vibration white finger syndrome
- **Atherosclerosis
- **Hyperviscosity (e.g. Cold haemmagglutinin disease, Cryoglobulinaemia)
- Hypothyroidism
- Anaemia (more often exacerbate rather than precipitate RP)
- Thoracic outlet syndrome
- ***Drug-induced (e.g. β blockers, Bleomycin)
***CTD presenting with Raynaud’s phenomenon
- ***Systemic sclerosis (most common)
- MCTD
- uCTD
- Sjogren’s syndrome
- Poly / Dermatomyositis
- SLE
- Necrotising vasculitis (e.g. Polyarteritis nodosa)
- RA (tend to be more focal, less systemic manifestations)
Systemic sclerosis
Definition:
- A **generalised (i.e. multi-system) disorder of connective tissue affecting skin + internal organs
- daily use: synonymous with **Scleroderma
- characterised by **fibrotic arteriosclerosis of peripheral + visceral **vasculature
- variable degrees of extracellular matrix accumulation (mainly collagen) occur in both **skin + **viscera
- associated with **specific AutoAb, most notably **Anti-Scl70 + ***Anti-centromere
Epidemiology:
- Uncommon condition
- Peak age of onset: 30-50
- F:M = 4:1
- Prevalence: 10-20 per 100,000
- Annual incidence: 1-2 per 100,000
- Geography: unrestricted
- Genetic predisposition: ?DR5, DR5w52, DR4
Clinical syndromes:
1. **Limited (cutaneous) SSc (LCSS) (70%)
- Skin involvement: Confined to areas of extremities below elbows / knees
- Less extensive systemic disease
- Comparatively better prognosis
- Associated with **Anti-centromere Ab —> ∴ able to prognosticate
- Previously known as ***CREST syndrome
-
**Diffuse (cutaneous) SSc (DCSS) (30%)
- Skin involvement: Proximal extremities (above elbow) / trunk below clavicles
- Higher risk for major organ involvement, esp. **pulmonary fibrosis, **scleroderma renal crisis
- Poor prognosis
- Associated with **Anti-Scl70, Anti-RNA-polymerase III Ab
Clinical features of Limited (cutaneous) systemic sclerosis (LCSS)
CREST syndrome:
1. Calcinosis cutis (Ca deposits in skin, extensor surfaces first ∵ prone to trauma / repeated use)
2. Raynaud’s phenomenon
3. Esophageal dysmotility (dysphagia, acid reflux)
4. Sclerodactyly (∵ skin tightening of fingers)
5. Telangiectasia (long blood vessels widening)
Clinical features of Diffuse (cutaneous) systemic sclerosis (DCSS)
- ***Cold-induced vaso/veno constriction
- RP
- Severe acrocyanosis
- Digital ischaemia
- Digital gangrene - ***Diffuse cutaneous involvement
- Calcinosis cutis
- Skin tightening
- Contracture of hands
- Microstomia - GI
- ***Esophageal —> dysphagia, acid reflux causing esophagitis, stricture, bleeding, nocturnal aspiration
- Small bowel —> bloating, abdominal cramps, intermittent / chronic diarrhoea, intestinal obstruction, pseudo-obstruction, malabsorption
- Large bowel —> constipation, diverticular disease - Musculoskeletal
- ***Polyarthritis (~RA): 20-30% with erosion
- Digital tuft resorption
- Low grade myositis - Cardio-pulmonary
- Dysrrhythmia
- Cardiac failure
- **Progressive fibrotic lung disease (HRCT: ground glass (suggestive of active disease), honeycomb (late fibrosis))—> Secondary pulmonary hypertension
- **Pulmonary hypertension (∵ thickening of pulmonary vasculature) - Renal
- **Scleroderma renal crisis (∵ intrarenal arterial stenosis —> abrupt malignant HT, oliguric RF (Ryan Ho))
- **Accelerated HT
- ***Renal failure (∵ thickening of renal vasculature) (avoid withdrawing steroid treatment abruptly —> can also precipitate acute renal failure)
Treatment of Systemic sclerosis
“No drug has been proven to be totally useless until it has been tried in systemic sclerosis”
“Some drugs may not be as useless in systemic sclerosis”
Treatment: Largely ***symptomatic
- Systemic sclerosis-associated ILD
- Systemic corticosteroids + Cyclophosphamide / Mycophenolate
- Nintedanib (TKI (Anti-fibrotic agent))
- Tocilizumab (Anti-IL6 receptor monoclonal Ab, potentially useful for skin manifestations) - Raynaud’s phenomenon
- Keep warm
- Avoid cigarettes / vasoconstrictors
- **Vasodilators (CCB, PGI2 / analogues (Iloprost), PDE inhibitors (Sildenafil))
- **Stellate ganglion block (SpC Med PP) - Cutaneous involvement (no drugs proven useful)
- Penicillamine
- Colchicine
- γ-interferon - GI
- ***PPI / H2 blockers
- Drugs that improve gut motility
- Antibiotics (for bowel flora overgrowth) - Musculoskeletal
- Polyarthritis: NSAID, **Anti-malarials (Hydroxychloroquine: anti-inflammatory activity)
- Low grade myositis: **Prednisolone Low dose - Cardio-pulmonary
- Dysrrhythmia: Anti-arrhythmic
- Lung fibrosis: **Steroid + Immunosuppressive for early disease
- Pulmonary HT: **Vasodilators (as per for RP), O2, **Endothelin-1 antagonist, **PDE5 inhibitor - Renal
- Accelerated HT: ***ACEI
Potentially disease remitting drugs:
- Endothelial modulators (e.g. PGI2, tPA)
- Immune modulators for inflammatory complications (e.g. Methotrexate, Mycophenolate, Cyclosporin A, Tacrolimus)
- Anti-fibrotic agents with limited evidence (e.g. Penicillamine, Colchicine, γ-Interferon, Anti-TGFβ)
- Specific inhibitors (e.g. Endothelin receptor antagonists)
Sjogren’s syndrome
Definition:
- A slowly progressive, inflammatory autoimmune disease affecting primarily the ***exocrine glands (~Mumps)
—> Lacrimal gland: Keratoconjunctivitis sicca
—> Salivary gland: Xerostomia
—> Trachea: Xerotrachea
—> Labial gland: Vaginal dryness
—> Pancreas: Pancreatitis
- ***Lymphocytic infiltrates replace functional epithelium leading to decreased exocrine secretions (Exocrinopathy)
- Characteristic AutoAb, **Ro(SS-A), **La(SS-B), ***RF are produced
Epidemiology:
- More common than systemic sclerosis
- All ages: 40-50 peak
- F:M = 9:1
- Prevalence unknown (∵ Primary + Secondary)
Classification:
1. **Primary Sjogren’s syndrome
- may be as common as SLE
- Immune-mediated keratoconjunctivitis sicca complex **without features / evidence of other underlying CTD (e.g. RA, SLE, SSc)
- Primarily glandular features
-
**Secondary Sjogren’s syndrome
- Immune-mediated keratoconjunctivitis sicca complex + **Confirmed underlying CTD
- ~30% of RA, SSc have at least histologic evidence of Sjogren
- ~2-3% of patients with CTD have focal lymphocytic infiltrates of the labial minor salivary glands
- Primarily features of the CTD (i.e. more systemic features)
Clinical features of Sjogren’s syndrome
Disease of exocrine glands:
1. Mucosal dryness
- Keratoconjunctivitis sicca
- Xerostomia —> Dental caries / gingival diseases, Dysphagia
- Xerotrachea —> Frequent URTI
- Vaginal dryness —> Dyspareunia, Vaginal infections
- Major salivary gland enlargement
- Atrophic gastritis, Pancreatitis
Features of autoimmunity:
1. AutoAb
2. Cytopenia (esp. Leukopenia)
3. Glomerulonephritis (∵ Immune complex deposition)
Extraglandular diseases:
1. **Non-erosive polyarthritis
2. Raynaud’s without telangiectasia / digital ulceration
3. Lung: Bronchitis, ILD
4. Kidneys: **RTA (Type 1), GN
5. Blood vessels: Vasculitis
6. Muscles: Low grade myositis
7. ***Risk of Lymphoid malignancy: usually Low grade lymphoma (∵ from Polyclonal B cell activation (in Exocrinopathy) evolve into Monoclonal B cell activation when 1 clone becomes more dominant)
Investigations of Sjogren’s syndrome
- Demonstration of mucosal dryness
- **Schirmer’s test
- **Rose Bengal staining
- ***Slit lamp examination (shallow corneal ulceration)
- Sialography, Sialometry - Demonstration of lymphocytic infiltration (Confirm the Dx)
- Major / Minor parotid gland swelling - Demonstration of autoimmunity
- **Hyperglobulinaemia
- High Ig
- **Positive RF (>90% in Primary Sjogren vs 60% in RA) (RF: AutoAb (IgM) interacting with IgG)
- ***Positive Anti-Ro (60%), Anti-La (40%)
- Leukopenia
- Thrombocytopenia
Treatment of Sjogren’s syndrome
- Mucosal dryness
- **Artificial tears, saliva
- **Cholinergic agonists (Cevimeline) (for dry mouth)
- Ensure dental hygiene
- Prompt treatment of superficial infections
- ***Vaginal lubricants - Systemic illness (As per SLE treatment)
- **Steroids (0.5-1 mg/kg/day of Prednisolone) + **Immunosuppressive drugs (e.g. Cyclophosphamide for interstitial pneumonitis, GN, vasculitis, peripheral neuropathy)
- Lymphoma: treatment depend on histological type
Dermatomyositis, Polymyositis, Dermatomyositis sine myositis (Dm sine myositis / Amyopathic dermatomyositis)
Definition:
- A member of CTD family as evidenced by autoimmune disease associations and other immunologic features
- Characterised by chronic inflammation of striated muscles (Polymyositis) and sometimes skin (**Dermatomyositis)
- **AutoAb associations (e.g. **Anti-Jo1, Anti-Mi2, **Anti-MDA5)
—> define homogeneous clinical subsets of disease
—> associated with development of ILD (Anti-MDA5: **rapid development of ILD + **high mortality (90% mortality within 6 months))
Clinical features of Dermatomyositis, Polymyositis, Dermatomyositis sine myositis (Dm sine myositis / Amyopathic dermatomyositis)
DM sine myositis / Amyopathic dermatomyositis:
- Skin manifestations alone
(- ***Anti-MDA5 associated (SpC Medicine))
Polymyositis:
- Myositis alone
Dermatomyositis:
- Both
Diseases:
1. Childhood idiopathic disease
2. Adult idiopathic disease
3. Associated with other CTD
4. Associated with underlying malignancy (older age / predominant skin manifestations —> higher chance)
Clinical features:
1. Proximal muscle
- **Painless proximal muscle weakness +/- Rash (Hallmark feature)
- **Elevation of serum muscle enzymes (CK most notably)
- Acute / Insidious onset
- Shoulder, Pelvic girdle involvement common
- Neck muscle weakness
- Bulbar muscle involvement (poor prognosis)
- Cutaneous
- Photosensitive rash (more generalised, can involve nasolabial fold vs SLE)
- Heliotrope rash (reddish purple rash on or around the eyelids)
- Gottron’s patches (pathognomonic, scaly erythematous lesions over MCP, PIP joints)
- Calcinosis cutis
- Digital vasculitis
- Machinist’s hands
- Raynaud’s phenomenon - Other musculoskeletal
- Polyarthritis - Pulmonary
- **Lung fibrosis (associated with **Anti-Jo1 Ab) -
**Malignancy (in elderly population) —> must do **Malignancy screen
- **NPC (in HK)
- Bronchus
- **Breast
- Stomach
- **Ovary
- **Cervix
- Prostate
Investigations of Dermatomyositis
Demonstrate **skin involvment, **muscle involvement, ***autoimmune involvement
- Typical clinical features (provide most clues)
- Skin biopsy (sometimes needed)
- Myositis (2 out of 3)
- **Elevated muscle enzymes: CPK, LDH, AST
- **EMG
- ***Muscle biopsy - AutoAb
- Anti-Jo1 (ILD-related)
- Anti-Mi2
- Anti-MDA5 (Amyopathic dermatomyositis, **Rapidly progressing ILD, Skin involvement e.g. **Digital ulcer, Correlate with disease activity (SpC Medicine))
(- Anti-NXP2 (Cancer-related)
- Anti-TIF1G (Cancer-related)
- Anti-SRP
(SpC Medicine)) - Malignancy screen
- Mandatory esp. in elderly
(- Nasoendoscopy
- USG + Mammogram
- CT TAP
- Pap smear
(SpC Medicine))
Treatment of Dermatomyositis
Myositis:
1. **High dose Steroid + Immunosuppressive drugs (e.g. Azathioprine, Methotrexate, Cyclophosphamide)
2. **IV IgG (for refractory disease)
3. ***Anti-CD20
4. Physiotherapy, Speech therapy
5. Percutaneous gastrostomy
Cutaneous involvement:
1. Moderate to High dose Steroid + Immunosuppressive drugs
2. Topical steroids
3. Hydroxychloroquine (good for photosensitive rash)
4. Vasodilators (for Raynaud’s)
Polyarthritis:
1. NSAID
Lung Fibrosis:
1. High dose Steroid + Immunosuppressive drugs
Malignancy:
1. Treat as appropriate (may cause regression of dermatomyositis (SpC Medicine))
Juvenile arthritis
Synonymous:
- Juvenile chronic arthritis (JCA) (EULAR)
- Juvenile rheumatoid arthritis (JRA) (ACR)
- Juvenile idiopathic arthritis (JIA) (ILAR)
Definition: **<16 yo, **>=6 weeks, unknown etiology (UpToDate)
Presents with ***different disease patterns
Types of JIA:
1. ***Polyarticular (>=5 joints) (30-40%)
- RF +ve
- RF -ve
- ***Pauciarticular (<=4 joints)
- Type 1 (associated with ANA iritis): Girls > Boys
- Type 2 (associated with HLA B27): Boys > Girls - ***Systemic onset (i.e. Still’s disease (UpToDate))
- Enthesitis-related JIA (UpToDate)
- Psoriatic JIA
- Undifferentiated JIA
Polyarticular onset JIA
- Subset of JIA defined by presence of **>=4 affected joints during **first 6 months of illness
- comprises 30-40% of patients with JIA
- presentation may be similar to ***RA in adults —> may also develop into RA in adulthood
- subclassified by presence / absence of ***RF
(Epidemiology:
- F>M
- Clear bimodal distribution:
—> First peak in incidence: 2-5 yo
—> Second peak: 10-14 yo
Clinical features:
Children <10 yo:
- ***Symmetrical joint involvement common: knees, wrists, ankles most frequently affected
- Uveitis can occur although much less common than children with Pauciarticular JIA
- ANA +ve patients are at greater risk for uveitis than ANA -ve patients
- Presentation tend to gradually improve, may grow out of it
Children >=10 yo:
- most children with Polyarticular onset JIA are RF -ve
- RF +ve children: follow pattern of **gradual disease progression as seen in **RA adults
- Presentation tend to progress into adult RA)
Pauciarticular onset JIA
- Involvement of ***<=4 joints
- F>M
- Peak incidence: 2 / 3 yo (i.e. ***younger)
Clinical features:
- **Larger joints (vs RA) are affected (knees, ankles, wrists, elbows) but virtually never begins in hips —> behave more like **Spondyloarthritis
- **Uveitis, but other systemic manifestations are characteristically **absent —> ∴ fever / rash / other constitutional symptoms suggest other diagnosis
Prognosis:
- Several long term complications occur
1. **Uveitis (need ophthalmology follow up) —> may lead to cataract (∵ topical steroid treatment), irregular pupil
2. **Leg length discrepancy (∵ large joint involvement)
Systemic onset JIA (SoJIA)
Most difficult to diagnose
Clinical features:
1. **Arthritis
- although necessary for a definitive diagnosis, may **not be evident early in the course of the disease
- any number of joints may be involved
—> most typical: wrists, knees, ankles
—> others: hands, hips, cervical spine, TM joints —> micrognathia, cervical spine fusion common in chronic disease
-
Constitutional symptoms +++
- **ill-looking, high spiking fever (Quotidian fever (i.e. fever for a few hours every day) (Felix Lai)), rashes, high WBC, anaemia (normochromic normocytic) —> must consider other DDx (*infection, leukaemia (∵ high WBC))
- very ill when febrile, but improve dramatically when temperature is normal - Skin
- macular, ***salmon pink rash (brought out by heat, prominent during fever) - **Hepatomegaly, Splenomegaly, **Lymphadenopathy
- ***Serositis
- Pericarditis: small pericardial effusion
- Pleuritis: pleural effusion - Neurological
- Chronic headaches, other neurological symptoms
Investigations:
- **ESR, CRP exceedingly high
- **Ferritin (APR) exceedingly high
Treatment:
1. **NSAID (Naproxen, Ibuprofen)
2. **Steroids
- Intra-articular injections are useful (long term: joint damage)
- Systemic steroids should be avoided (long term: growth stunting)
3. **Methotrexate
4. Anti-TNFα, Anti-IL6
5. Autologous HSCT
6. **Physical / Occupational therapy
- maintenance of joint function
—> splints
—> ROM exercises (active / passive)
—> posture / prone-lying exercises
- adequate rest / exercise
—> balanced physical activity
—> selected peer sports (tricycle / swimming)
Course / Prognosis:
- arthritis **resolves in ~40-50% of children
- if child is well after **6 months —> ***likely to remain well
- 1/3 children with systemic JIA remain ill for prolonged period of time —> guarded prognosis
Vasculitis: Approach
Consider the parts affected:
1. ***Blood vessel itself (e.g. Aneurysm)
- ***Organ supplied
- Large vessel:
—> Temporal artery: Headache
—> Aorta: Aneurysm
- Small vessel:
—> Skin: Vasculitic skin rash
—> Kidney (glomerulus): GN
—> Nervous system: Peripheral neuropathy - ***Systemic manifestations
- Fever
- Constitutional symptoms
***Vasculitic syndromes
Primary vasculitis:
- Large vessel disease
1. Giant cell arteritis
2. Takayasu’s arteritis
- Medium vessel disease
1. Kawasaki disease
2. Polyarteritis nodosa (PAN) (Hep B related) - Small vessel disease:
ANCA-associated small vessel disease:
1. Granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis)
2. Eosinophilic granulomatosis with polyangiitis (EGPA) (Churg Strauss syndrome)
3. Microscopic polyangiitis (MPA)
Immune complex small vessel disease:
1. IgA vasculitis (Henoch Schonlein purpura)
2. Hypocomplementaemic urticarial vasculitis (Anti-C1q vasculitis)
Secondary vasculitis:
1. SLE
2. RA
3. Sjogren’s syndrome
4. Behcet’s disease
5. Essential mixed cryoglobulinaemia
