L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
Pediatric Rheumatology
L. Nandini Moorthy, MD MS
Assistant Professor of Pediatrics
Chief, Division of Pediatric Rheumatology
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson
Medical School
New Brunswick, New Jersey, USA
Case 1: One swollen joint
A three year old Caucasian girl with a one month history of swollen left knee
 No history of fevers
 No rash
 No weight loss
 No other joints are involved
 CBC and differential within range
 CMP, ESR, CRP, Ig within range
 LDH within range
 ANA titre 1:320
 RF negative
Most likely diagnosis is Oligo-articular onset JIA ~Pauciarticular JIA (PaJIA)
 Commonest subtype (› 50%)
 1-5 years of age
 Girls > boys
 Arthritis in ≤ four joints
 Large joints-knees, ankles, elbows
 Usually spares hips
 Rarely affects wrists, & small joints of hands & feet
Differential Diagnosis of PaJIA
 Reactive arthritis
 Lyme arthritis
 Septic arthritis
 Trauma
 Neoplastic disease
 Dactylitis (< 4 ?psoriatic arthritis)
PaJIA-Course and Complications
 Benign course, good prognosis
 Recurrences ~ 20%
 May progress to extended-oligoarticular arthritis requiring aggressive treatment
 Discrepancy in limb lengths
 Persistent inflammation
 Orthotic/surgical correction
 Fixed flexion contractures
 PT & OT
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
Case 2: Many swollen joints
Consider the case of a 6 year old girl who presents with multiple swollen joints,
morning stiffness and mild anemia
Most likely extended Oligoarticular JIA~Polyarticular JIA (PoJIA)
 30% -40% of JIA
 Girls > boys
 Bimodal peaks: 2-5 years & 10-14 years
 Insidious onset, sometimes acute, with progressive involvement of >/=5 joints in
the first 6 months
 In younger children, onset is usually pauciarticular
 AM stiffness and fatigue
 May have low-grade fever
 Arthritis intermittent or persistent
 RF+ve or RF-ve
 Small joints of hands & feet
 Tenosynovitis of flexor tendon sheaths
PoJIA
 Labs - normal or suggest an inflammatory state
 Anemia
 High ESR
 Hypergammaglobulinemia
 Leukocytosis
 5-10% RF +
 40-50 % ANA + [Cassidy, 2001]
 Late-onset PoJIA
 Subset of RF+ girls mimics adult RA
 Chronic course into adulthood
PoJIA-Differential diagnosis
 Infectious causes of polyarthritis
 Viral
 Septic
 Lyme
 Other
 Serum sickness
 Other rheumatic diseases
 Inflammatory Bowel Disease (IBD)
 Systemic Lupus Erythematosis (SLE)
 Dermatomyositis
 Sarcoidosis
 Scleroderma
 Spondyloarthropathies (enthesitis, axial involvement)
 Rarer causes
 Malignancy
 Other immunodeficiences
PoJIA-Course & Complications
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Guarded prognosis
Poorer prognosis
Adolescent girls RF+ with late-onset, rapidly progressive erosive arthritis –often
have RA like disease as adults
Early involvement of small joints of hands & feet
Persistent inflammation
Subcutaneous nodules
RF +
Destructive hip disease among other joints & eventual disability
Contractures & ankylosis
Short stature (more in children)
Often require joint replacements
Chronic uveitis – 5%
SoJIA- Course & Complications
 Systemic features may persist for 4-6 months with varying degrees of joint
involvement
 Prognosis
 Complete recovery
 Polyarticular pattern
 Persistent inflammation &/ or chronic destructive arthritis
 Long standing SoJIA
 Micrognathia, c-spine fusion and destructive hip disease
 Short stature & FTT
 Uveitis - rare
 Amyloidosis -rare in the US
 Macrophage Activation Syndrome
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Enthesitis-related arthritis /Spondyloarthropathy
Commonly complain of:
 Pain in the back & heel
 Morning stiffness
 Arthritis & /or enthesitis with any 2 of the following:
 Sacroiliac joint tenderness, Inflammatory spinal pain or both
 Positive family history
 Acute anterior uveitis
 Arthritis onset in boys > 8 yrs
 HLA-B 27 (higher likelihood of developing debilitating ankylosing spondylitis)
Pathogenesis of JIA
 Cytokine dysequilibrium -- increased IL-1, TNF
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Management
 NSAIDS
 Disease Modifying Agents (DRUGS)
 Joint Replacement
 Physical and Occupation therapy
 Ophthalmologic monitoring
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Social support, education and family counseling
NSAIDS
 Naproxen
 Nabumetone
 Diclofenac
 Indomethacin
 Ibuprofen, Naprosyn and Tolmentin are approved for children
 Used for all types
 Usually sufficient for PaJIA, mild spondyloarthropathy & mild cases of other
types.
 Follow LFTs, UA
 Watch for GI, skin and psychiatric symptoms
Disease Modifying Anti-Rheumatic Drugs (DMARD) or
Slow Acting Anti-Rheumatic Drugs (SAARDS)
 Cyclophosphamide
 Leflunamide (Arava)
 Thalidomide-in SoJIA
 Tacrolimus
 Novel Biologics
 Gold
 Autologous bone marrow transplantation –in severe cases of SoJIA
 Monitor- LFTs, CBC, UA, BP, neuropathy
 NOVEL BIOLOGICS
 Anti-TNF agents
 Etanercept is a recombinant fusion dimeric protein (sTNFR)
 Infliximab -Monoclonal Anti-TNF antibody (has murine componenmt)
 Combination of Etanercept and Methotrexate
 Adalimumab (Humira): Fully humanized TNF alpha Mab with human derived
heavy and light chain variable regions and human IgG constant regions.
 Anakinra (Kineret): IL-1 Receptor antagonist blocks cellular activation
 Anti-IL-6R ab: Anti-IL-6 receptor antibody prevents the formation of IL-6/IL-6R
complex and eventually inhibits the function of IL-6 in children with SoJIA
 Adverse events
Cases 3, 4 and 5: The swollen joint
 All three children have an unremarkable exam except for arthritis
 Complete blood count and differential, electrolytes, blood urea nitrogen,
creatinine, and urine analysis are within normal limits
 Erythrocyte sedimentation rate range from 30-40 mm/hour
 The X-rays of the respective joints show only soft tissue swelling
 They were all started on non-steroidal anti-inflammatory drugs
 Diagnosis and management
 Patient 3 tested positive for Lyme Western Blot IgG; Treated with oral
Doxycycline for Lyme disease.
 Patient 4 had elevated Antistreptolysin-O titre and anti-strep-DNAse B
antibodies and had normal electrocardiogram and echocardiogram; Started on
oral Penicillin treatment and prophylaxis for Post-Streptococcal Reactive Arthritis.
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Patient 5 had stool culture positive for Salmonella; Treated with Amoxicillin for
Reactive Salmonella Arthritis.
Reactive & infection-related arthritis
 Viral: Ebstein Barr Virus, Rubella, Parvovirus, Hepatitis, Mumps, Herpes, HIV,
Echovirus
 Bacterial: Poststrepococcal arthritis, Rheumatic fever, Gonococcal, Chlamydia,
Yersinia, Salmonella, Shigella, Campylobacter, Mycoplasma, Clostridium
 Lyme disease
 Septic, Tuberculosis, Fungal, Protozoal
 Reiter’s syndrome
Reactive arthritis
 Non-specific arthritis after an extra-articular infection with one of the arithritogenic
bacteria such as Chlamydia, Shigella, Salmonella, Yersinia or Campylobacter
 Here the term encompasses arthritis related to extra-articular infections
 Berlin Diagnostic Criteria
 Typical peripheral arthritis PLUS
 Evidence of preceding illness
 Exclude juvenile idiopathic arthritis and other arthritis of known causes
 Usually clinical features characteristic of primary infection
Should know the clinical findings of
 Acute rheumatic fever: erythema marginatum
 Diffuse rash
 Polyarticular disease
 Rash, pustule, and bulla
 Bull’s eye rash
Case 6: A teenage Asian girl with 3 month history of malar rash
 She also presented with:
 Palatal ulcers
 Photosensitivity
 Fatigue
 Myalgias and arthralgias
 Mild anemia
 ANA titre of 1:320
Some facts
 Incidence: 0.36 -0.9 per 100,000 per year
 Prevalence: <1- 4.5% of patients in pediatric rheumatology
 Age: Childhood onset 15-17 %, Rare (but still occurs) below 5 years
 Sex: More in females (Male:Female ratio 1:4.5)
 In younger age group, the ratio is almost equal
 Race: African-American, Hispanic, Asian
 Genetics: Family and Twin studies
 Etiology: Unknown!!! Genetic-abnormalities in immune function regulationEnvironmental –Hormonal
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
Clinical presentation
 Fever, fatigue, weight loss, irritability
 SKIN
 Malar rash-Fixed erythema, flat or raised, over the malar eminences, tending to
spare the nasolabial folds
 Discoid rash-Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur in older lesions
 Other types of rash, nail involvement, hair loss (alopecia)
Renal involvement in SLE
 Clinical nephritis in 75% of children, blood in the urine (hematuria- cannot always
see with your eye-need to get urine tests with your physician), swelling, high BP
a) Persistent proteinuria greater than 0.5 grams per day or grater than 3+ if quantitation
not performed
OR
b) Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed
Serositis
a) Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or
evidence of pleural effusion
OR
b) Pericarditis--documented by ECG or rub or evidence of pericardial effusion
Cardiac - inflammation of different parts of the heart (pericarditis, myocarditis,valuvilitis),
Myocardial infarction
Lungs
Central Nervous System
20-40% of affected children, depression, difficulty in concentrating, cognitive impairment
(~52% of children), lupus headache, seizures etc.
a) Seizures--in the absence of offending drugs or known metabolic derangements; e.g.,
uremia, ketoacidosis, or electrolyte imbalance
OR
b) Psychosis--in the absence of offending drugs or known metabolic derangements, e.g.,
uremia, ketoacidosis, or electrolyte imbalance
Laboratory exam
 General
 Hematologic disorder
 Hemolytic anemia--with reticulocytosis OR
 Leukopenia--less than 4,000/mm<>3<> total on 2 or more occasions OR
 Lyphopenia--less than 1,500/mm<>3<> on 2 or more occasions OR
 Thrombocytopenia--less than 100,000/mm<>3<> in the absence of offending
drugs
 Evidence of immune dysfunction
 Bleeding and clotting abnormalities
 Liver functions
 Sedimentation rate (inflammation)
 Blood and protein in urine
 Low complements- C3, C4
Autoantibodies -ANA, Anti-ds-dna, ENA
Antiphospholipids
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
Immunologic disorder
a) Positive LE cell preparation OR
b) Anti-DNA: antibody to native DNA in abnormal titer OR
c) Anti-Sm: presence of antibody to Sm nuclear antigen OR
d) False positive serologic test for syphilis known to be positive for at least 6 months and
confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody
absorption test
Approach to management
General
Routine/flare-worsening
Team approach
Adequate rest
 Sun-protection
 Immunizations
 Prompt management of infection
 Subspeciality visits
 Call doctor prior to any procedure-may need extra antibiotics or steroids
 Evaluate mood (patients may get depressed!!!)
MEDICATIONS
Steroids
Cyclophosphamide
Methotrexate
Cyclosporin
Rituximab
Hydroxychloroquine
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Hydroxychloroquine toxicity
Prognosis
Infections, steroid complications, atherosclerosis
New treatments and better survival
Survival has improved in the past 20 yrs
10-year survival approaches 90%
Extent of organ involvement (renal, central nervous system), apparent vasculitis,
and multisystemic character of the disease
Sepsis (severe life-threatening infection) is the commonest cause of death
Important determinants: families’ ability to cope, socioeconomic status,
compliance, teen-related issues, contraception
Atherosclerosis
Case 7
Juvenile Dermatomyositis (JDM)
 Vasculitis frequent & often severe
 Calcinosis common in recovery phase
 Polymyositis uncommon
 Malignancy rare
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Epidemiology
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
 Incidence: 0.5 per 100, 000/year
 ~20% Onset in childhood
 4-10 years; Boys 6 years; Girls 6, 10 years
 F:M - 1.4:1 to 2.7:1; higher for >/=10yrs
 Widely distributed
 Blacks > Whites
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Clinical features
 Constitutional: Fever 38-40C, easily fatigued, anorexia, malaise, wt loss
 MSKS: symmetric proximal- weakness of LE limb girdle; anterior neck
flexors/back & abdo, Gowers
 Pelvic girdle- stairs, Trendelenburg- weak hip adductors
 Severe (10%)
 Threat of aspiration
 DTRs usually nl
Clinical features
 Visceral vasculitis (pancreatitis, melena, hematemesis, perforation)- poor
prognosis--rapidly leads to death
 Also gall bladder, bladder, uterus, vagina, testes, retinitis, mild GN
 Cardiopulmonary
 Lipodystrophy ~20% (assoc. with insulin resistance)
 Diagnosis
 Proximal muscle weakness
 Classic rash
 Elevated serum muscle enzymes
 Electromyographic changes
 Histopathology
Lab tests
 Leukocytosis, anemia -rare unless GI bleed
 High CRP, ESR
 Microscopic hematuria
 IgA, IgG, IgE
 CPK, AST, Aldolase, LDH
 ANA ~10-85%
 MSA & MAA
MRI
 T1-fibrosis, fat infiltration, atrophy
 T2-fat suppressed-edema/inflammation
EMG
Muscle biopsy
Treatment
 Steroids
 Hydroxychloroquine
 Methotrexate, Cyclosporine, Cyclophosphamide, Azathioprine, anti-TNF
 IVIG
 Plasmapheresis
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Supportive care
PT, OT
Course & Prognosis
 Prodrome-progressive-persistent-recovery
 Monocyclic, Chronic ulcerative, Chronic non-ulcerative
 Poor: severe disease activity, cutaneous ulcerations, calcinosis, distal
involvement, dysphagia/dysphonia, nailfold changes, noninflammatory
vasculopathy, specific MSAs
 Long term survival >90%
Rheumatology Case 8
3 year old boy with a 3 day history of swollen, painful ankles
 No fever
 Physical examination normal except for swelling, pain on motion, warmth,
tenderness of both ankles
 Found on routine laboratory tests to have moderate hematuria, heavy proteinuria
Vasculitis
 Characterized by size of vessel
 Large (Takayasu)
 Medium and small (Kawasaki, PAN)
 Small (SLE, JDM, serum sickness, hypersensitivity, HSP, neoplasm associated)
 Characterized by cellular infiltrate
 Giant cells (Takayasu, WG)
 Neutrophils with nuclear debris (HSP)
 Clinically distinct (HSP, Kawasaki, WG)
 Serologically distinct (ANCA associated – MPA, WG)
 Antineutrophilic cytoplasmic antibodies (ANCA)-cytoplasmic and perinuclear
HSP
At least one of the following 4 should be present:
1. Diffuse abdominal pain
2. Any biopsy showing predominant IgA deposition
3. Arthritis or arthralgia
4. Renal involvement (any hematuria and/or proteinuria)
In the presence of Palpable purpura (mandatory criterion)
Henoch-Schonlein Purpura
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Cutaneous manifestations occurs in 96-100%
Palpable purpuric lesions
Dependent/pressure bearing areas
Acute, symmetric, erythematous, macular or urticarial
Coalesce to form palpable purpura
Occur in crops and change color from red to purple to brown
Clinical Features
GI involvement (1-4 weeks) in 75%
Abdominal pain (80%): colicky, periumbilical
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
 Vomiting, abdominal distention
 Melena, hematemesis, ileus
 Submucosal bleeding
 Intussusception (3%), ileoileal (easily missed by barium enema)
 Mesenteric vasculitis
 Rare: pancreatitis, gallbladder hydrops, pseudomembranous colitis
 Genitourinary complications
 Musculoskeletal involvement (50-85%)
 CNS vasculitis
 Thrombotic complications
 Brain infarcts (IgA APLA)
Renal disease in 47%
 NS
 Transient hematuria
 97% in the first 3 months of disease
 Focal or segmental mesangial proliferation to cresentric
 44% of children presenting with nephritic/NS –may have high BP
 Risk factors for renal disease:>4 years of age, GI bleeding, Purpura >1 month
 Risk factors for unfavorable renal outcome: Hypertension, Proteinuria, Nephritis,
Renal failure at disease onset
 Renal failure can develop up to 10 years after onset
 1-5% may develop ESRD
Labs:
 High WBC, platelets, anemia, guaic +ve stools, high IgA, high IgA ANCA
 D/D- ITP, Acute post strep, SLE, Septicemia, DIC, HUS, Acute Hemorrhagic
edema
 Opposite: IgA deposition in skin
 Recurrence is 16-40% (6wk-2yr)
 Prognosis is usually excellent
Treatment
 Usually none or supportive with acetaminophen, NSAIDs
 Short term steroids (initially IV) for severe GI, urologic manifestations (no RPCT)
 1-2 mg/kg/d for 1 week then taper over 2-3 wks
 Renal prophylaxis with steroids?
 Severe renal disease: pulse steroids, azathioprine or cyclophosphamide,
urokinase plus warfarin, IVIG, plasmapheresis
 (Wang et al)
Case 9
Kawasaki Disease
An acute febrile illness of childhood with medium and small sized necrotizing vasculitis
first described by Kawasaki in 1967
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KD – other clinical
Arthritis/arthralgia (acute, subacute, convalescent phases)
Large weight bearing joints, PIPs (?edema)
Meningitis, irritability
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Pneumonitis
Iritis
Gastroenteritis, watery diarrhea
Meatitis, sterile pyuria, priapism
Otitis, cough, coryza
KD- other clinical features
 Hydrops of the gallbladder
 Encephalopathy, seizures, ataxia
 Intestinal ischemia, infarcts
KD Phases
 Acute febrile period lasting approximately 10 days (range 5-25d).
 Associated rash, carditis, mucous membrane, conjunctiva, adenitis
 Subacute period of approximately 2-4 weeks
 Arthritis, perineal and extremity desquamation, coronary artery aneurisms
 Convalescent phase lasting months
 Nail changes, aneurisms, arthritis
Pathogenesis
 Postulated theories
 Infectious/Viral
 Superantigen
 Cytokine related
 Aberrant immune response triggered by a pathogen acquired through respiratory
route
 Oligoclonal antigen driven response
 Endothelial cell activation, CD68+ monocyte/macrophages, CD8+ (cytotoxic)
lymphocytes, and oligoclonal IgA plasma cells appear to be involved.
 Subtle maturational defect in immune responsiveness
 Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 (Burns et al)
KD
 M>F
 6-11 months
 Asians>Europeans
 Acute febrile, subacute, covalescent
 CAA in ~ 5%; many develop coronary artery ectasia
 Giant aneurysms (>= 8 mm)
 Stenotic leading to MI
 Rupture acutely or develop later thrombosis due to stasis of blood flow and the
procoagulant endothelial surface
 ? Anticoagulant therapy
GOALS OF TREATMENT
 CONTROL INFLAMMATION
 PREVENT ACUTE MORBIDITY, MORTALITY
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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o Coronary aneurysms
o Peripheral gangrene
o Myocardial infarct
PREVENT CHRONIC MORBIDITY
THERAPY
 ASA 80 to 100 mg/kg per day in 4 doses with IVIG for 3-14 days
 High-dose ASA and IVIG appear to possess an additive anti-inflammatory effect.
 Low-dose ASA (3 to 5 mg/kg per day) until no evidence of coronary changes
 For children with coronary abnormalities, aspirin may be continued indefinitely
 Naproxen
 IVIG (2 g/kg) with aspirin (50–80–100 mg/kg) given within 10 days of fever onset
 Second infusion of IVIG (2 g/kg) in addition to high-dose aspirin is strongly
recommended in all children with persistent or recurrent fever
 How to treat the small group (3–4%) still remaining febrile?
 Either a third dose of IVIG (2 g/kg)
 Corticosteroids
 Cyclophosphamide, cyclosporin and ulinastatin
 Anti-TNF agents (Infliximab)
o Weiss J, Eberhard A, Chowdhury D, Gottlieb B, J Rheum, 2004
IVIG TREATMENT OF KD:CLINICAL EFFECTS OF IVIG
REDUCES CAA’S, MORTALITY, Newburger JW et al, NEJM 1991: 324:1633
REDUCES GIANT CAA’S, Rowley AH, Duffy CE, Shulman ST, J Pediatr 1988;
113:290
AMELIORATES DISEASE AFTER DAY 10, Marasini M et al, Am J Cardiol 1991;
68:796
o
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o
Approximate 10% failure rate, 67% respond to retreatment, 22% of 2nd
IVIG failures respond to 3rd
Studies only show efficacy with regards to CAA if initiated before 12 days
Toxicity
< 30% side effects (aseptic meningitis, hyperviscosity syndrome, ?
recurrence)
blood product-historical problem with hepatitis C transmission
Cost: $100 + per gram
Case 10: 10 year old black male with cough and weight loss for one month
 Fever for one month
 Increasing tiredness and myalgias
 Asthma exacerbation
 Unable to exercise or play as much as he used to
 Palpable bilateral non-tender cervical lymph nodes
 Hepatomegaly with mild tenderness
 Mild wheezing on auscultation
 Lymphopenia and anemia
 Normal ESR, CRP 4.2 mg/dl
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
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Negative for HIV, Hepatitis A, B, C and Parvovirus and TB
Serum calcium 9.1 mg/dl (8.5 - 10.5)
Sarcoidosis
 Older vs. Younger children
 Asymptomatic
 Clinical presentation can vary greatly
 Older children --- multisystem disease similar to the adult manifestation, with
frequent hilar lymphadenopathy and pulmonary infiltration.
 Early-onset childhood sarcoidosis --- triad of rash, uveitis, and arthritis in patients
presenting before age 4 years.
 Lofgren's syndrome - EN, bilateral hilar adenopathy, joint symptoms
Pediatric Sarcoidosis
 Lymphadenopathy -most common
o Intrathoracic - 75 to 90%
o hilar nodes bilaterally
o unilateral enlargement
o paratracheal nodes
o Peripheral - cervical, axillary, epitrochlear, inguinal
o Non-tender, non-adherent, with a firm, rubbery texture
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Chronic cough (2nd most common)
Parenchymal disease (infiltrates, effusions, atelectasis), restrictive
Half with pulmonary symptoms
Dyspnea, cough, chest pain
20% with abnl CXR and minimal/ no symptoms
Diagnosis
 Anemia ~ 5%
 Leukopenia ~ 30%
 Eosinophilia ~ 25%
 Thrombocytopenia
 High ESR with EN, acute phase
 Hypercalcemia, hypercalciuria ---2-63%
 High Bili, Alk phos
 Proteinuria ---30%
 ACE
 Kveim test
 CXR, Gallium
 BAL --- high Lymphocyte count and macrophages; high CD4/CD8
 High IL-1B, IL-6, TNF alpha
 Anergy to PPD
 Biopsy- Non caseating granuloma
Case 11: Is it a rash?
 Shiny, thickened and discolored skin
 Linear scleroderma/Morphea
L. Nandini Moorthy, MD MS
Handout- Peds Rheumatology
Case 12: Should know Raynauds
Blanching of hands
Case 13: Systemic Sclerosis
 Major criterion - sclerodermatous skin changes affecting areas proximal to the
metacarpophalangeal or metatarsophalangeal joints
 Minor criteria are as follows:
 Sclerodactyly
 Digital scars resulting from digital ischemia
 Bibasilar pulmonary fibrosis not attributable to pulmonary disease
 Diffuse: Interstitial pulmonary fibrosis; Anti Scl 70 ab
 Limited (CREST): Pulmonary hypertension; Anticentromere ab
Other topics
 Hypermobility syndrome
 Functional joint complaints
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Disorders of connective tissue
Marfan syndrome
Ehlers-Danlos syndrome