1. Department of Rheumatology and Clinical Immunology
Saturday clinical meeting 13 Feb 16

2. Patient particulars 40 year old male
Residing at Thane, hailing from Chennai
Graduate
Engineer by occupation
History given by self and reliable

3. Chief Complaints Bluish discoloration of fingers x Apr 14
Ulcer over tip of both middle fingers x Nov 14

4. HOPI Firstly pallor followed by bluish discoloration lasting 10 min.
Frequency – 2-3 times/month
Aggravated on exposure to cold
Relieved by wearing gloves.

5. RAYNAUD’S PHENOMENON

6. Pathophysiology of Raynaud's
Cold induced Alpha 2 c receptor mediated vasoconstriction involving Rhokinase signalling pathway. Cold stimulates mobilization of alpha 2 c from golgi complex to cellular membrane

7. Classification of Raynaud's

8. HOPI Cont… Ulcer - Right middle finger – Nov 14 Painful, Pruritis +
Incidentally noted
Gradually progressive over last 6 months
Presently size of a button
Not associated with any discharge
Painful, Pruritis +
Partial response to topical ointments/antibiotics
Similar ulcer over left middle finger – Nov 14
Spontaneous resolution in 3 months

9. D/D – Digital Ulcer Collagen autoimmune disorders
Trauma
Infectious Disorders
Leprosy
Collagen autoimmune disorders
APLA Syndrome
Vasculitis
SLE
MCTD/ UCTD
Autonomic endocrine causes
Diabetes
Buerger’s Thromboangitis obliterans
Raynaud’s disease
Poisoning
Mercury : pink discoloration , Acrodynia

10. Ulcers in CTD Occur in about 31.8–71.4% (median 45.2%).
14–29% -progress to gangrene and autoamputation
Early phase -ulcers are localised on
-fingertips
-malleoli
-heel
-great toe
Disease progression-ulcers over bony prominences
Provoked by mechanical retraction of the skin, especially on the dorsal aspect of the IP joints & elbows
Exposed to repetitive trauma at sites of chronic contractures

11. Fingertips ulcers Complication of RP and chronic ischemia
Both with limited or diffuse SSc
Usually ulcers heal slowly and become portals for
infections
gangrene
bone involvement - osteomyelitis
refractory cases-digital amputation

12. Derived from Digital pitting scar
Hyperkeratotic
Small (2-3 mm)
Localised on the fingers
White/yellow
Undermined
Continuously painful

13. Ulcers characterised by loss of tissue
Different sites that may deepen down to the bone
Undermined
Painful.
When they occur over bony prominences they are due to tissue retraction

14. Ulcers due to calcinosis
Defined as deposits of calcium phosphate in soft tissues, visible to the naked eye and/or confirmed by x-ray
May occur anywhere
Variable dimension
Hard
Adherent to the bottom of the ulcer or tissues
Painful
Complicated by infection
With or without fistulisation

15. According to depth - Partial thickness skin loss involving epidermis.
1. Superficial:
- Partial thickness skin loss involving epidermis.
- Ulcer is superficial
- Presents clinically as abrasion/blister/tiny crater.
Intermediate:
- Full thickness skin loss
- Damage to/necrosis of subcutaneous tissue
- May extend down to, but not through, underlying fascia.
- Presents clinically as a deep crater with or without undermining of adjacent tissue.
Deep:
- Extensive destruction, or damage to tendon, joint capsule and bone

16. Negative history
No h/o orogenital ulcers, joint pain, hair or nail involvement
No eye/urinary/ genitals involvement
No h/o Cough/ breathlessness/ chest pain/ palpitations.
No h/o dysphagia/Jaundice/pain abdomen/weight loss
No h/o Headache/ syncope/ seizure/ weakness of limbs.
No h/s/o intermittent claudication

17. Past History
H/o smear and culture negative radiographic Pulmonary Koch’s for which pt received 6 months of ATT – years back
No DM/HTN/Asthma

18. No significant family history
Personal history
Non smoker and non alcoholic
Regular bladder and bowel habits
Normal appetite and regular sleep pattern
Family History
No significant family history

19. TREATMENT HISTORY Topical applications
Oral antibiotics without much relief.

20. SUMMARY
Middle aged male with past h/o pulmonary Kochs presented with two years h/o Raynaud's phenomenon and recurrent digital tip ulcers.

21. Differential diagnosis
Collagen vascular diseases-
Scleroderma
SLE
UCTD
MCTD
Overlap syndromes ???
Thromboangitis obliterans

22. ACR CRITERIA for Scleroderma
MUST HAVE (a) OR TWO OF (b),(c) OR (d) (a)Proximal SSc (proximal to MCP/MTP) (b)Digital pits (c)Sclerodactyly (d)Pulmonary fibrosis 98% specificity

23. Scleroderma pattern of disorders
lcSSc-skin inv only distal to the elbows and knees
dcSSc-skin thickening proximal to the knees and elbows.
SSc sine scleroderma -vascular and sero features of SSc without any skin involvement

24. CREST
Calcinosis, Raynaud’s phenomenon, Oesophageal dysmotility, Sclerodactyly, and Telangiectasis) syndrome
An outdated term for lcSSc
Should not to be used as a synonym for limited SSc because many patients with lcSSc do not develop all the features of CREST.
Does not recognise important complications of this subset including PAH, mid-gut disease and lung fibrosis.
SSc can also overlap other autoimmune diseases
such as SLE/DM/RA (overlap syndromes).

25. SLICC CLASSIFICATION CRITERIA
Clinical & Immunological criteria
Classify a patient as having SLE if he or she satisfies
4 of the clinical and immunologic criteria used in the SLICC classification criteria, including at least one clinical criterion and one immunologic criterion,
OR if he or she has biopsy-proven nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies.
Petri, M., et al. (2012), Derivation and validation of the Systemic Lupus International
Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis &
Rheumatism, 64: 2677–2686.

26. CLINICAL CRITERIA Acute cutaneous lupus Chronic cutaneous lupus
Oral ulcers OR nasal ulcers
Non scarring alopecia or hair fragility with visible broken hairs)
Synovitis involving 2 or more joints, characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness
Serositis

27. CLINICAL CRITERIA
7. Renal Urine protein–to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours OR red blood cell casts
8. Neurologic
9. Hemolytic anemia
10. Leukopenia (<4,000/mm3 at least once) / Lymphopenia (<1,000/mm3 at least once)
11. Thrombocytopenia (<100,000/mm3) at least once

28. IMMUNOLOGIC CRITERIA ANA level above laboratory reference range
Anti-dsDNA antibody level above laboratory reference range (or >2-fold the reference range if tested by ELISA)
Anti-Sm: presence of antibody to Sm nuclear antigen
Antiphospholipid antibody positivity as determined by any of the following:
Positive test result for lupus anticoagulant
False-positive test result for rapid plasma reagin
Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)
Positive test result for anti–β2-glycoprotein I (IgA, IgG, or IgM)
5 Low complement
Low C3, Low C4, Low CH50
6 Direct Coombs' test in the absence of hemolytic anemia

29. Undifferentiated Connective Tissue Disease
UCTD
MCTD
SLE
SSc
DM/PM
SJOGREN’S SYNDROME
Pts present with features of a connective tissue disease but do not fulfil the current criteria for a specific CTD are diagnosed UCTD

30. Clinical features of UCTD
New onset Raynaud’s phenomenon
Nailfold capillaroscopy abnormalities
With or without autoantibodies
Multiple clinical and serological features of rheumatic diseases
do not allow diagnosis of specific entity
Features strongly suggestive of particular rheumatic disease
Do not meet the criteria

31. Clinical features UCTD
SYMPTOMS PERCENTAGE
Raynaud’s phenomenon – 80
Arthralgias
Arthritis
Sicca symptoms
Alopecia
Photosensitivity
Malar rash
Sclerodactyly
Leukopenia
Thrombocytopenia
Anemia

32. Overlap syndrome SLE SSc MCTD IIM RA
Sharps syndrome(1972). Described as a CTD with distinct feautres of SSc/polymyositis and SLE
High titres of anti-U1-RNP autoantibodies further defined this disease
IIM RA

33. PERIPHERAL VASCULAR DISEASE
Skin changes (thinning, shiny, or paleness)
Weak pulses / gangrene
Non healing ulcers
Toes that turn blue
Severe burning pain
Leg cramps and pain
Muscles that feel numb or heavy
Toe nails - thick and opaque
Insufficient tissue perfusion initiated by existing atherosclerosis acutely compounded by either thrombus or emboli. Affects blood vessels outside heart and brain

34. General Examination Wt - 55kg, Ht-165 cm, BMI- 20.05Kg/sqm Afebrile
Pulse: 78/min, regular, normal volume and character with no R-R/R-F delay. All peripheral pulses well felt.
BP: 124/86 mmHg Rt arm supine position. No significant difference in BP in other limbs.
RR 18/ min, regular, abdo thoracic.

35. General Examination Blackish discoloration of digits present
No Pallor/Icterus/Clubbing/ Lymphadenopathy/ Pedal edema
Digital tip ulcer over right middle finger of size 1.0x0.5 mm with black margins and dry with no discharge.
Acral sclerosis ++
No plantar ulcers or any ulcers over body.

36. Ulcer

37. Systemic Examination RS: PA: Soft, non-tender no palpable organomegaly
Chest expansion 4 cm
Bilateral basal Velcro crackles heard.
PA: Soft, non-tender
no palpable organomegaly
CVS: S1S2 normal, no murmur
CNS: HMF-normal, no focal neuro-deficit

38. Summary
Middle aged male with past h/o Pulmonary Kochs presented with h/o recurrent digital tip ulcers and Raynauds phenomenon. Examination revealed b/l velcro crackles on chest auscultation.

39. Clinical diagnosis
SSc
SLE
Overlap ( SSc + SLE)

40. Investigations CBC- WNL LFT/ RFT : WNL ESR: 64 mm fall in 1 hr
CRP : Positive

41. Investigations Lipid profile – normal BSL (F/PP) – 92/137 mg/dl
Urine RE/ME – NAD
24 hrs urinary protein & urinary protein/albumin ratio- WNL
ANA- Positive,
RF – positive by latex
Anti CCP Ab - Negative

42. Investigations C3/C4 complement level- WNL Sr ACE & p-ANCA – WNL
Anti U1 RNP, Sm & Ro-52 Ab- Strongly positive
ECG, X Ray chest and both hands- WNL
Spirometry - restrictive pattern
USG Abdomen- Cholelithiasis
CT Aortogram - Normal
HRCT Chest- No features of ILD

43. HRCT FINDINGS in ILD with CTD
Interlobular septa
Subpleural cysts
Honeycombing
Subpleural micronodules,
Small airway ectasia (bronchiectasis and bronchioloectasis)
GGO - correlates to the presence of air space inflammation and alveolitis.

44. ILD with CTD

45. ANA

46. Extractable Nuclear Antigen
Extractable Nuclear Antigens are over 100 different soluble cytoplasmic and nuclear antigens.
Autoantibodies to these antigens are associated with particular connective tissue disorders.
The six main antigens used in immunological laboratories for detection are : Ro, La, Sm, RNP, Scl-70 and Jo-1, which are screened for by double immunodiffusion techniques and confirmed by immunoblotting.

47. U1RNP
MCTD was initially described as a connective disease with high titres of autoantibodies directed against a complex named “ribonuclease- sensitive extractable nuclear antigen”.
Further studies revealed that the specific antigen of these autoantibodies is the U1 ribonucleoprotein complex, a part of the spliceosome.

48. Spliceosome are nuclear particles that process pre messenger RNA
The immunogenic potential of splicesosomal components may be increased by post translation modifications during apoptosis
The small nuclear ribonucleo-protein particles (snRNP) and the heterogeneous nuclear ribonucleo-protein particles (hnRNP), two spliceosomal subunits, are the major targets of autoimmunity.
SnRNP contain small RNA ranging from nucleotides complexed with proteins
U1 RNP are a subset of SnRNP with high amt of uridine

49. The U1-RNA molecules form double-stranded secondary structures, which make up the backbone of the U1-RNP complex.
The protein components of the U1-RNP complex can be further classified as proteins specific for the U1-RNP complex and non-specific proteins.
Specific proteins are U1-A, U1-C and U1-68 kDa- proteins.
Non-specific proteins include the Smith proteins (Sm proteins) and the SR proteins, a group of splicing factors rich in serine (S) and arginine (R).
Autoantibodies against U1-RNP and other snRNPs mainly recognize the protein components of the complex.
Sm-proteins are common targets of autoimmunity in SLE, whereas patients with MCTD usually express high antibody titres for the U1-68 kDa protein.

50. Nail Fold Capillaroscopy
micro and macro thrombi evident over cuticle and proximal nail folds, s/o disrupted vasculature

51. NFC
Nailfold capillary microscopy has an impressive cost/effectiveness ratio:
simple
Safe
non-invasive
inexpensive.

52. Ways to perform NFC ophthalmoscope, stereomicroscope, photomacrography
videocapillaroscopic systems

53. Parameters assessed haemorrhage loss of capillaries
presence of enlarged and giant capillaries
haemorrhage
loss of capillaries
disorganization of the vascular array
ramified/bushy capillaries

55. Nail fold capillaroscopy
A, active SSc pattern (magnification 200×); B, pattern observable in patients with UCTD (magnification 200×); C, with DM (magnification 200×) and D, with APS (magnification 200×).

56. Nail fold capillaroscopy

57. Final diagnosis
MCTD

58. Leucopenia/thrombocytopenia
Kasukawa Criteria
Common symptoms
Raynauds
Swollen fingers
SLE
Polyarthritis
Adenopathies
Malar rash
Serositis
Leucopenia/thrombocytopenia
SSc
Sclerodactyly
Pulm fibrosis and/or restrictive changes and/or reduced DLCO
Oesophageal hypomobility ordilatation PM
Muscle weakness
Elevated muscle enzymes
Myogenic changes in EMG
Serologic criteria
Anti snRNP antibodies
If > 1 common symptom plus > 1 symptom of the mentioned signs of >2 of the defined CTD(sle,ssc and PM) plus serologic criteria

59. MANAGEMENT

60. Treatment of Raynaud’s
Dihydropiridine-type calcium channel blockers(oral nifedipine)-first-line therapy
intravenous iloprost-severe SSc-related RP .

61. Treatment of Digital ulcers
Topical and systemic treatment.
Intravenous prostanoids (i.v. iloprost) and nifedipine -healing digital ulcers.

62. Bosentan & digital ulcers
Appears more effective in patients with ≥ 3 active digital ulcers at treatment outset
Fewer new ulcers
Does not speed healing of digital ulcers- the cardinal ulcer persisted in 50% of all subjects for up to 24 weeks.
These data suggest that chronic endothelin receptor antagonism has an important effect on peripheral vascular integrity and function in systemic sclerosis

63. SSc ulcers-standard treatment
Wash with sterile solution
Disinfection of the lesion
Mechanical removal of fibrin
Induction autolysis of necrotic tissue and induced repair is necessary in order to recreate an appropriate microenvironment (humidity).
For that reason any medication that will block the gas exchange and formation of humidity (greenhouse effect- restore the microclimate) should be avoided:
“closing” the ulcers may facilitate infection that spread rapidly into the tissue, and the circulation (septicemia).
In case of infections it is necessary to identify the microbial agent through a biopsy, in order to establish a promt systemic antibiotic treatment

64. Management of case Tab Ecosprin 150mg OD Tab Pentoxyphylline 400mg TDS
Tab Diltiazem SR 90mg OD
Tab Bosentan 62.5 mg OD
Tab Folic acid 5mg OD

65. Follow-up
90 % improvement in symptoms
Under regular follow up.

66. MCTD Sharps syndrome(1972)
Described as a CTD with distinct feautres of SSc/polymyositis and SLE
High titres of anti-U1-RNP autoantibodies further defined this disease
Later, a high prevalence for the development of arthritis resembling RA pattern was observed in patients with MCTD.

67. The clinical features of MCTD often develop over several years and, the complete clinical findings are rarely present in the beginning of the disease
C/F
Raynaud’s phenomenon,
Puffy fingers of the hands,
Sclerodactyly,
Arthralgias, arthritis, myalgias,
Myositis and malaise.

68. Genetic associations Associated with HLA DR1,HLA DR4 AND HLA DR2
SLE –assoc with HLA DR2 AND HLA DR3
SSc-HLA DR3 AND HLA DR5
PM-HLA DR3
Since the initial description, several authors challenged the concept of MCTD as a distinct clinical
entity for the following reasons [32]:
First, most patients diagnosed with MCTD also satisfy the criteria for another connective tissue disease, especially in later stages of the disease.
Second, there isn’t any commonly accepted set of criteria for the classification of MCTD, although several criteria sets have been tested successfully.
Third, the initial description of MCTD as a benign connective tissue disease not involving major organ systems and promptly responding to low-dose corticosteroids has not been confirmed by other studies.

69. SLE v/s MCTD
Serological features also support the concept of MCTD as a distinct disease entity.
Although 20 to 30 % patients with SLE might also express anti-U1-snRNP antibodies, per definition a sine qua non for the diagnosis of MCTD, high titres of these antibodies are specific for patients with MCTD .
Furthermore, SLE patients with anti-U1-snRNP antibodies often retain IgM-U1-snRNP, instead of showing a class switch to IgG antibodies as found in MCTD .
Finally, anti-U1-RNP antibodies in patients with SLE seem to differ from patients with MCTD in terms of antigen recognition

70. Clinical manifestations with high titres of anti-U1-snRNP antibodies
Rarely develop
Severe CNS (e.g., psychosis, seizures)
Renal manifestations (e.g. diffuse proliferative glomerulonephritis.
They develop
RF-positive, erosive arthritis more frequently.
Pulmonary arterial hypertension

71. MCTD Pro Contra • Association with certain HLA types
• High titres of IgG anti-U1-RNP antibodies with unique antigen recognition
• Specific set of clinical manifestations
Contra
• Patients might satisfy the classification criteria of other CTDs in later stages of the disease
• Not one commonly accepted set of criteria

72. Apart from anti-U1-RNP antibodies, a variety of other antibody specificities including, anti-Ro/SS- A antibodies, anti-hnRNP-A2 antibodies, antiphospholipid antibodies and antibodies against other components of U1-RNP complexes, may be present in patients with MCTD.
Antigen spreading to molecules in close proximity of the original antigen (i.e., the U1-RNP complex) could play a role

73. For MCTD, there is not one commonly accepted set of classification criteria.
So far, four different classification criteria for MCTD are available, i.e. the criteria of Sharp, Alarcon- Segovia, Kahn, and Kasukawa
Since none of those criteria has convincingly been shown to be superior to the others, all four criteria are currently used.

74. SHARPs CRITERIA
1. Severe myositis 2. Lung involvement with a DLCO < 70 % and/or PAH and/or proliferative vascular lesions on biopsy 3. Raynaud’s phenomenon and/or oesophageal hypomobility 4. Swollen hands and/or sclerodactyly 5. anti-ENA ≥ 1 : 10000, positive for anti-U1-RNP antibodies and negative for anti-Sm-antibodies

75. Alarcon-Segovia’s criteria
CLINICAL CRITERIA
1. Swollen hands
2. Acrosclerosis with or without proximal SSc
3. Raynaud’s phenomenon
4. Myositis: biologically or histologically proven
Synovitis
SEROLOGIC CRITERIA
Anti-RNP-antibodies with a titer of > 1 : 1600 at the hem-agglutinin assay
Diagnosis of MCTD, if the serologic criterion is present and ≥ 3 clinical criteria (if 1, 2 and 3 are present, 4 and 5 are also required to distinguish MCTD from SSc)

76. Kahn criteria CLINICAL CRITERIA SEROLOGIC CRITERIA RAYNAUDS
SWOLLEN FINGERS
MYOSITIS
SYNOVITIS
SEROLOGIC CRITERIA
HIGH TITRES OF ANTI RNP AB CORRESPONDING TO SPECKLED ANA TITRE OF >1:2000
SEROLOGIC CRITERION IS PRESENT PLUS RAYNAUDS PLUS ≥2/3 CLINICAL CRITERIA