1. Connective Tissue Diseases

2. Connective tissue diseases (CTDs) are defined as a group of acquired diseases resulting from persistent immune mediated inflammation.
Generation of autoreactive T cells or autoantibodies.
Autoantibodies/autoreactive T cells can attack any organ of the body, resulting in a wide array of signs and symptoms.

3. The classic autoimmune CTDs include:
Systemic lupus erythematosus (SLE),
Juvenile dermatomyositis/polymyositis
(JDM/PM), systemic sclerosis (SSc),
Sjögren’s syndrome (SS),
undifferentiated CTD (UTCD)
overlap syndromes (mixed CTD (MCTD)

4. The clinical presentation of CTD in childhood can range from an acute severe illness mimicking a serious infection, to an insidious onset of disease with gradual accumulation of symptoms and signs over weeks to months.
Should suspect CTD when a child has a multi system disease with no apparent cause.

5. Other clinical features that suggest CTD include:
prolonged fever,
oral ulcers,
Raynaud’s phenomenon,
Skin rash (malar rash, Heliotrope rash, nodules), photosensitivity,
alopecia,
pleuropericarditis,
glomerulonephritis,
arthritis,
unexplained abdominal pain,
muscle weakness,
sicca symptoms (dry eyes and dry mouth)
Constitutional symptoms(fever, anorexia, muscle ache, fatigue and weight loss)

6. Systemic Lupus Erythematosus
Multisystemic autoimmune disease of unknown etiology
In most basic terms lupus is an autoimmune disease with autoantibodies to self nuclear antigen in various tissue leading to organ damage
More common in females
Prepubertal 4:1
Postpubertal 8-9:1

7. SLE Criteria  4/11 Malar Rash Discoid Rash Photosensitivity
5 Organ Systems
CNS
Seizure
Psychosis
Serositis
Kidney
Proteinuria
Arthritis
Non erosive
Hematologic
Lymphopenia (<4,000)
Lymphopenia (<1,500)
AIHA
Thrombocytopenia (<100,000)
4 Skin
Malar Rash
Discoid Rash
Photosensitivity
Oral Ulcers
2 Immunologic
ANA
dsDNA, anti-Smith, antiphospholipid antibodies
In order to make the dx must have 4 of the 11 criteria. The criteria include cutaneous findings, immunologic findings, as well as organ specific manifestations.
Malar rash – fixed erythema, flat or raised, spares nasolabial folds
Serositis – pericarditis, pleuritis, peritoneal surfaces leading to abdominal pain
NON-erosive arthritis
Renal: persistent proteinuria or cellular casts

8. In order to make the diagnosis, must have 4 of the 11 criteria at one time or over period of observation.

9. Clinical Features Hematological system:
Thrombocytopenia, Auto immune hemolytic anemia, Leucopenia, lymphopenia;
Renal disease:
Nephrotic syndrome, Acute nephritis, Hypertension;
Central nervous system involvement:
Seizures, Psychosis, Stroke, Organic brain syndrome,Chorea
Lung disease:
Pleural effusion or acute/chronic pneumonitis;
Cardiovascular system:
Pericarditis, myocarditis, Libman Sacks endocarditis;

10. Mucocutaneous disease:
Photosensitivity, malar rash, alopecia, oral and nasal ulcers;
Gastro-intestinal involvement:
GI vasculitis, sterile peritonitis;
Musculoskeletal:
Arthritis, arthralgia, myalgia, inflammatory myositis.

11. Discoid Lupus Well-circumscribed, red-purplish, elevated plaques
Discoid lupus may be part of the systemic form of SLE, or may be the hallmark of DLE (discoid lupus erythematosus where patients have cutaneous manifestations in absence of systemic findings). These are Well circumscribed, elevated plaques with advancing borders of scale.
May show some depigmentation
Most frequently on face and scalp (especially behind ears)

12. Malar Rash Spares nasolabial folds
The malar rash typically occurs in the Photosensitivity distribution
The rash is typically Erythematous, sometimes scaly patch
Not specific for SLE-also seen in dermatomyositis
Spares nasolabial folds

13. Oral Ulcers Gingivitis, mucosal hemorrhage, erosions, and ulcerations
Most commonly found on the hard palate and are painless!
10-15% of SLE patients

14. Malar rash and ulcers on the lips in a child with SLE

15. Differantial Dx
The important differential diagnosis to be considered are:
Infections (bacterial and viral),
Malignancy,
Vasculitis,
Chronic granulomatous diseases like sarcoid and autoinflammatory syndrome.

16. Treatment NSAIDS Hydroxychloroquine (Plaquenil) Steroids
Ototoxic, ocular side effects
Steroids
Immunosuppressants
Cyclophosphamide
Azathioprine
Cellcept
Sunscreen
Treatment of SLE is complicated and again depends on many factors including organ manifestations. In addition to medications such as hydroxhycloroquine, steroids, and immunosuppressive medications, these patients must adhere to lifestyle modifications such as daily use of sunscreen.

17. Neonatal Lupus Maternal Transfer of Antibodies Complications Treatment
Anti-Ro (SS-A)
Wane at 6 mo
Even with asymptomatic mom’s
Complications
Rash
Heart block – usually 3rd degree
50 % of babies born to moms with SLE
Damage and scarring during 2nd trimester
Not reversible
Hepatitis
Neutropenia/thrombocytopenia
Hydrops fetalis
Treatment
Supportive
May need cardiac pacing
Neonatal lupus is the one of the rare occassions you will see a pediatric rheumatologist in the NICU. This is a condition that is noted in neonates due to maternal transfer of antibodies, specifically anti-RO (SSA). Interestingly, these mothers are often healthy and without any autoimmune symptomology. The transplancental passage of this antibody, whose levels tend to wane at 6 months, may lead to significant complications. The most important of these are 3rd degree heart block which will require cardiac pacing and is due to the attack of fetal cardiac myocytes. Typically, this complication occurs in the end of the 1st-2nd trimester of fetal development, such that this is an irreversible process. Other complications, include rash (which I will show you in th next slide), heptatiis, neutropenia/thrombocytopenia, and hydrops fetalis. Typically these patients are treated supportively and in the case of the rash are given sun protection advise as the rash is photosensitive. Mothers with known SLE, and with previous infants with heart block are monitored throughout prgnancy with fetal echocardiography.

18. Neonatal Lupus Raccoon Eyes Annular Scaling Annular plaques
The mean age of onsetof rash is 6weeks,but can be as late as 3 months…with new lesions rarely occur after 3 months
The rash, and antibodies will typically clear by 6-12 months and there are no lasting effects bc maternal IgG antibodies are cleared by the infant
Approx 1/4 have lasting scarring/atrophy/depigmentation/telangiectasias
Annular plaques

19. Congenital Heart Block
NLE is the most frequent cause of congenital heart block!
Occurs in 25-30% of affected patients

20. Drug Induced Lupus D-SLE Others Most often reversible ANA
D = Drugs for the Heart (procainimide)
S = Sulfonamides
L = Lithium
E = Epilepsy medications (anticonvulsants)
Others
INH
Minocycline
Most often reversible
ANA
Anti-histone Ab
Important to know are medications which may cause drug induced SLE. These drugs include procainadmide, sulfonamides, lithium, anticonvulsants, INH, and monocycline. These patients will have indistinguishable features from patients with SLE, and may even have similar serologies, butwill typically have anti-histone antibodies. The removal of the offending agent will lead to reversibility in the majority of these patients.

21. Juvenile Dermatomyositis (JDM)
Myopathy and Vasculopathy
MyopathySymmetrical proximal muscle weakness
Vasculopathy  Skin Manifestations
Another interesting, and rare disorder is JDM. This is a myopathy which presents as symmetrical proximal muscle weakness, as well as a vasculopathy typically with cutaneous manifestations.

22. The age of onset has two peaks, between 5 and 9 yrs and between 11 and 14 yrs, with a predominance of females
Heliotrope rash on the eyelids, Gottrons papules on the knuckles and proximal muscle weakness are the classical features of JDM.

23. Clinical Manifestations
Insidious in onset
Constitutional Symptoms
Fatigue
Fever
Weight loss
Muscle weakness
Physical Findings
Heliotrope Rash
Photosensitive rash – upper torso, extensor surfaces of arms/legs
Nail fold telangiectasias
Gottron papules
Gower’s sign
Dysphagia/dysphonia/dyspnea
Nodular calcifications
The onset is typically insidious, and patients will present with constitutional symptoms such as fever, fatigue, weight loss, and muscle weakness. Muscular wekaness may also lead to dysphagia/dysphonia and dyspnea in severe cases. On physical examination, heliotrope rash, photosensivie rashes, nail fold telangiectasias, Gotrrons papules, and nodular calcifications are presents.

24. Heliotrope Rash Violaceous hue Periorbital edema Malar rash
The heliotrope rash presens as a violaceous rash on the upper and lower eyelids There may be periorbital edema as well. The malar rash associated with JDM may or may not spare the nasolabial folds.
Malar rash

25. Gottron’s Sign Pathognomonic for JDM
Pathognomonic for JDM is the Gotrons signs which presents as red, thickened scaly skin that overlies the PIPs, and MCPs.
Red,thickened, scaly skin
overlying PIPs

26. Nail fold dilation and loops
Calcinosis
Striae
Othe cutaneous manifestations include a photosensitive rash, and calcinosis. These are subcutenaous calcium deposits, which are disfiguring and may also lead to contractures depending on their location. They are very difficult to treat, and may be the nidus for infections when they rupture leading to oozing of a white toothpaste like material. Surrgical removal often leads to recurrence and medications are not usually helpful. A simple way to evaluate for vasculopathy is manification of the capillaries surrounding the nailbed using a device known as a dermatoscope. Typical findings may include capillary dilation and loops.
Photosensitive Rash
Nail fold dilation and loops

27. JDM: Work Up & Treatment
Labs
Increased CK, Aldolase, LDH, AST, ALT
Increased vWF Antigen
Usually nl ESR/CRP
+ ANA at times
Radiology
MRI
EMG
Treatment
Sunscreen
Steroids
Methotrexate
IVIG
Complications
At high risk of gastric perforation
Typically these patients will have elevated muscle markers, and depending on their presentation may have normal inflammatory markers. Myopathy may be present on specially protocolized MRIs which show increased T2 signals within the thighs. However, the GOLD standard remains findings of necrosis, edema and inflammation on muscle biopsy. Treatment includes suncreen, and immunosuppressive medications.

28. Scleroderma
The most characteristic feature of scleroderma is thickening of the skin due to increased collagen deposition.
Two main categories:
Localized scleroderma (morphea): there is skin sclerosis but usually no vascular or internal organ involvement,
juvenile systemic sclerosis: there is diffuse skin sclerosis along with internal organ involvement.

29. Linear scleroderma
a form commonly seen in children where there is a longitudinal band of skin thickness leading to contractures.

30. Morphea Flesh colored, erythematous or purplish patches
Firm Hyperpigmented
plaque
Ivory plaque

31. Juvenile Systemic Sclerosis
extremely rare in children
Typically starts with Raynaud’s phenomenon
Skin involvement presents as skin thickening, hidebound skin, hyperpigmentation, contractures due to skin thickening. Later, the skin shows thinning of the skin and hypopigmentation.
The other symptoms include, heartburn, malabsorption, pulmonary fibrosis, pulmonary arterial hypertension and arthritis

32. Raynaud’s Phenomenon Sharp demarcation
-Characterized by pallor, cyanosis, and hyperemia with pain, burning, numbness, tingling, swelling, and hyperhidrosis of the affected fingers and toes.
-Precipitated by cold or emotional stress
-All pts with scleroderma, 10-30% of patiens with SLE, or primary disorder
-Recent review, 69% of patients had primary form.

33. CREST
Calcinosis
Sclerodactyly
Raynaud
Telangiectasia

34. Sjogren’s Syndrome probably the rarest
symptoms include dry mouth (difficulty in eating dry food and speech) and dry eyes besides systemic features
presence of autoantibodies (ANA, anti-SSA or anti-SSB antibodies)
lymphocytic sialedinitis on minor salivary gland biopsy.

35. Mixed Connective Tissue Disease (MCTD)
MCTD is a syndrome where clinical features of multiple CTDs are present along with presence of high titre anti-RNP antibodies.
Raynaud’s phenomenon is present in nearly 95% of patients.

36. Antibodies to extractable nuclear antigens in different connective tissue diseases