Connective tissue disorders (CTDs), a presentation in dermatology/rheumatology by Dr. Basil Tumaini and May Shoo

1. CONNECTIVE TISSUE DISORDERS
Dr. May Shoo
Dr. Basil Tumaini
2015
MMED Internal Medicine Residents
Muhimbili University of Health and Allied Sciences
1

2. SLE & DERMATOMYOSITIS
May Shoo
2

3. Lupus Erythematosus
• Lupus erythematosus is a name given to a collection of
autoimmune diseases in which the human immune system
becomes hyperactive and attacks normal healthy tissues.
• Lupus erythematosus may manifest as a systemic disease or
in a purely cutaneous form.
3

4. Classification
• Lupus has four main types:
• systemic
• discoid
• drug-induced
• neonatal
• Of these, systemic lupus erythematosus (SLE)
is the most common and serious form.
4

5. Categorization of lupus(skin manifestation)
includes the following types:
I. acute cutaneous lupus erythematosus
II. subacute cutaneous lupus erythematosus
III. chronic cutaneous lupus erythematosus
5

6. 1.Acute Cutaneous LE
• is characterized by erythema of the nose and malar eminences
in a “butterfly” distribution.
• A widespread involvement of the face as well as erythema and
scaling of the extensor surfaces of the extremities and upper
chest
• The erythema is often sudden in onset, accompanied by edema
and fine scale
• These acute lesions, last for days and are often associated with
exacerbations of systemic disease.
6

7. 7

8. 2.Subacute cutaneous lupus erythematosus
(SCLE)
Typical features include symmetric, widespread, superficial, and non-
scarring non atrophy lesions.
• Involvement of the neck, shoulders, upper chest, upper back, and
extensor surface of the hand is common.
• These lesions begin as small photosensitive, erythematous, scaly
papules or plaques that evolve into a papulosquamous
(psoriasiform) or annular polycyclic form.
• Is associated with the presence of anti-Ro/SS-A antibodies, genetic
deficiencies of complement C2 and C4, and certain medications,
such as hydrochlorothiazide.
8

9. 9

10. 3.chronic cutaneous LE
• AKA- Discoid lupus erythematosus (DLE), is characterized by discrete lesions,
most often found on the face, scalp, &/external ears
• The lesions are erythematous to violaceous papules or plaques with a thick,
adherent scale that occludes hair follicles (follicular plugging)
• When the scale is removed, its underside shows small excrescences that
correlate with the openings of hair follicles (“carpet tacking”), a finding
relatively specific for DLE
• Long-standing lesions develop central atrophy, scarring, and
hypopigmentation
• These lesions persist for years and tend to expand slowly
10

11. Facial discoid lupus rash with a
malar distribution.
Note the erythema (indicating
disease activity), keratin plugged
follicles, and dermal atrophy.
The characteristic pattern of
hyperpigmentation at the active
border and hypopigmentation at
the inactive centre is especially
evident in black patients.
Discoid lesions are usually found
on the face, scalp, ears or neck.
11

12. Systemic lupus erythematosus
• SLE is the prototypic multisystem autoimmune disorder with a broad
spectrum of clinical presentations encompassing almost all organs and
tissues
• SLE represents a syndrome rather than a single disease
• SLE is a chronic disease of variable severity with a waxing and waning
course, with significant morbidity that can be fatal if not treated early
in some patients
12

13. • SLE have disease onset between the ages of 16 and 55 years
• Women are affected nine times more frequently than men
• Men with lupus tend to have less photosensitivity, more
serositis, an older age at diagnosis, and a higher 1 year mortality
compared to women
13

14. CAUSES
1. Environmental factors: include ultraviolet light, demethylating drugs,
and infectious or endogenous viruses or viral-like elements. Eg:
i. sunlight
ii. Epstein Barr virus (EBV) interact with B cells and promotes IFNα
production by plasmacytoid dendritic cells (pDCs).
iii. certain drugs induce autoantibodies cause drug-induced lupus
(DIL) eg: procainamide and hydralazine, these drugs may alter gene
expression in CD4+ T cells by inhibiting DNA methylation and induce
over expression of LFA-1 antigen, thus promoting autoreactivity.
14

15. CAUSE……
2.Epigenetics effect: is inherited changes in gene expression
caused by mechanisms other than DNA base sequence
changes. Eg:DNA methylation and post-translational
modifications of histones, which plays a role in X chromosome
inactivation and certain cancer.
3.Hormonal factors - addition of oestrogen or prolactin can lead
to an autoimmune phenotype with an increase in mature
high-affinity autoreactive B cells eg: in pregnancy and OCP
user.
15

16. Pathogenesis of SLE
• The pathogenesis of SLE involves a multitude of cells and molecules
that participate in apoptosis, innate and adaptive immune responses.
• Immune responses against endogenous nuclear antigens are
characteristic of SLE.
• Autoantigens released by apoptotic cells are presented by dendritic
cells to T cells leading to their activation.
• Activated T cells in turn help B cells to produce antibodies to these
self-constituents by secreting cytokines such as IL10 and IL23 and by
cell surface molecules such as CD40L and CD 152
16

17. Patho………….
• Increased amounts of apoptosis-related endogenous nucleic
acids stimulate the production of IFNα and promote
autoimmunity by breaking self-tolerance through activation of
antigen-presenting cells.
• Once initiated, immune reactants such as immune complexes
amplify and sustain the inflammatory response
17

18. 18

19. SLE involves other systems
• Musculoskeletal features
 Arthritis/arthropathy- primarily affecting the small joints of
the hands,wrists, and knees.
 Myositis -Generalised myalgia and muscle tenderness are
common during disease exacerbations
 Avascular bone necrosis
19

20. OTHER……..
• Renal and hematological features: Proteinuria of various levels is
the dominant feature of lupus nephritis (LN) and is usually
accompanied by glomerular haematuria, and pancytopenia .
• Nervous system features : SLE aff ects both the central nervous
system (CNS) and the peripheral nervous system (PNS) (referred
to as neuropsychiatric SLE (NPSLE) syndromes)
• Cardiovascular ,Pleura and lungs features: myocariditis,
pericarditis,pleuritis,pleural effusion,pneumonitis etc.
• Git ,liver , lyphnode involvements etc
20

21. DIAGNOSIS
• Haematology( Leucopenia,mild anaemia,thrombocytopenia)
• Chemistry
• Urinalysis
• PT PTT INR/ Antiphosholipid antibodies
• Serology - ANA, ENA {(extractable nuclear antigens) including
anti-dsDNA†, complement†(C3 ,C4 ,and CH50).
• Boipsy of lesion/organ
• Chest x-ray, KUB US
• ECG, ECH0
• Other tests as suggested by history/symptoms 21

22. Dx of SLE can be clinical and laboratory based on ACR mnemonic of SLE
diagnostic criteria "SOAP BRAIN MD" mnemonic: The presence of 4 of the 11
critria
• Serositis
• Oral ulcers
• Arthritis
• Photosensitivity
• Blood disorders
• Renal involvement
• Antinuclear antibodies(95% sensitivity test)
• Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)
• Neurologic disorder
• Malar rash “butterfly” rash
• Discoid rash
22

23. • Systemic steroids-predniselone
• NSAIDs-Ibuprofen,diclofenac
• Immunosuppressive agents- azathioprine cyclophosphamide
• Antimalarials -hydroxychloroquine 400mg/day
• Sunscreens
• Anticoagulation therapy-in patients with thrombolytic
complications
Treatment
23

24. DERMATOMYOSITIS
• Is a connective-tissue disease characterized by
inflammation of the muscles and the skin.
May also affect the joints, the esophagus, the lungs,
and, less commonly, the heart.
CAUSES
Unknown however
• Genetic eg HLA DR3,4,5
• Immunology ABNOMAL T CELL
• Infectious pavovirus,coxsackievirus echovirus HIV
toxoplasma species borrelia spp
• Environment factors like drugs statins, penicillamine
quinidine,cyclophosphamide,Interferon
24

25. SIGN AND SYMPTOMS
Skin manifestation
• Eruption predominantly on photo exposed
surface
• Pruritic skin lesions
• Erythema of the mid face
• Eruption along the eye lid margin with or
without periorbital edema
25

26. • Eruption on dorsal hand particular over the
knuckles
• Change in the nail fold of the finger
• Eruption on the upper outer things
• Scary scalp or diffuse hair loss
26

27. • MUSCLE
Proximal symmetrical muscle weakness
Patients find it hard to raise their arms to comb
their hair or walk up the stairs due to the proximal
muscle weakness. It can be severe enough to
affect the muscles needed for speech and
swallowing and is also known to cause respiratory
compromise.
27

28. SYSTEMIC
• Fever, arthralgia, malaise, weight loss,
• Dysphagia
• GERD
• Dysphonia
• Atrioventricular defects, tachyarrhythmia, dilated
cardiomyopathies
• Git ulcers
• Pulmonary involvement due to weakness of thoracic
muscle
• Subcutaneous calcification which may result in contracture
of the ankle.
28

29. • Gotron lesions- erythematous scaly eruption
occurring in symmetric fashion over the MCP and
interphalangeal joints
• Heliotropic (purple) rash over the upper eyelids.
• Shawl (or V-) sign is a diffuse, flat, erythematous
lesion over the back and shoulders or in a "V" over
the posterior neck and back or neck and upper
chest, which worsens with UV light.
• Mechanic's hands- rough, cracked skin at the tips
and lateral aspects of the fingers forming irregular
dirty-appearing lines that resemble those seen in a
laborer
29

30. Gotron lesions
30

31. Gotron lesions
31

32. Heliotrope rash
32

33. Chest rash
33

34. Mechanic hands
34

35. Periungual involvement
35

36. Periungual involvement
36

37. Pathophysiology
• this is result of humoral attack against the muscle capillaries and
small arterioles.
• Specific antibodies activates Complement system lead to
membrane attack complex which are deposited in the endomysial
vasculature this will cause microscopic vessels damage with
muscle atrophy and later necrosis and degenerative fibers
Diagnosis
• Muscle biopsy:
-mixed B- and T-cell perivascular inflammatory infiltrate
-Perifascicular muscle fiber atrophy
• EMG
• Creatine phosphokinase (CPK)
37

38. Treatment
No known cure. Specialized exercise therapy may
supplement treatment to enhance quality of life.
• Sun avoidance
• Sunscreen and photoprotective clothing
• physiotherapy
• Prednisolone
• Methotrexate
• Mycophenolate
• Intravenous immunoglobulin
• Azathioprine
• Cyclophosphamide
• Rituximab
38

39. references
• Wallace D, Hahn BHH, eds. Dubois lupus erythematosus, 7th
edn. Lippincott Williams and Wilkins, 2007.
• Lahita G, ed. Systemic lupus erythematosus, 5th edn.
Amsterdam:Elsevier, 2011.
• Olasz EB, Yancey KB: Bullous pemphigoid and related
subepidermal
• autoimmune blistering diseases, in Current Directions in
Autoimmunity: Dermatologic Immunity, BJ Nickoloff, FO Nestle
(eds). Basel, Karger Press, 2008, pp 141-166
39

40. Scleroderma disorders
[from Gk: σκληρός+δέρμα]
skleros-hard, derma-skin
Dr. Basil B. Tumaini
40

41. Outline
• Introduction
• Pathogenesis
• Classification
• Clinical features
• Diagnosis
• Investigations
• Treatment
• Prognosis
• References
41

42. Introduction
The scleroderma disorders comprise a heterogeneous
group of conditions linked by the presence of
thickened, sclerotic skin lesions
• Female preponderance, F:M – 5:1
• Peak incidence: 30-50 years of age
42

43. Pathogenesis
• Susceptible host
• Triggering event
• Activation immune system
• Endothelial cell activation
• Activation fibroblasts
• The symptoms result from inflammation and
progressive tissue fibrosis and occlusion of the
microvasculature by excessive production and
deposition of types I and III collagen.
• Vascular dysfunction-small arteries and arterioles
43

44. Scleroderma-related disorders
Localized: morphea- circumscribed (plaque); linear;
generalized; mixed
Systemic: limited cutaneous SSc; diffuse SSc; SSc sine
scleroderma; overlap syndromes
SSc= systemic sclerosis
44

45. Limited vs Diffuse Scleroderma
Limited
• Most positive ANA
• 80% anticentromere
• Rare renal, heart, lung
involvement
• May develop PAH in
long standing disease
Diffuse
• 50% ANA positive
usually nucleolar
• Scl 70 in 30%,
correlates with
pulmonary fibrosis
• Renal crisis with RNA
polymerase
• Higher mortality
45

46. Morphoea
• Morphoea is a localized form of scleroderma with
pale indurated plaques on the skin but no internal
sclerosis
• Many plaques are surrounded by a violaceous halo
• It has good prognosis
• Fibrosis slowly clears leaving slight depression and
hyperpigmentation
46

47. Circumscribed Morphea
Pale indurated plaques
47

48. Linear morphea of the face
Slight depression and hyperpigmentation left
after clearing of fibrosis
48

49. Limited cutaneous scleroderma
• Raynaud phenomenon for years, occasionally decades
• Skin involvement limited to hands, face, feet, and forearms
(acral distribution)
• Nailfold capillary pattern typical of scleroderma predominantly
nailfold capillary loops with capillary dropout
• A significant (10 to 15 percent) late incidence of PAH with or
without skin calcification, GIT disease, telangiectasias (CREST
syndrome), or ILD
• Renal disease rarely occurs
• Anticentromere antibody (ACA) in 50 – 60%, but other patterns
also occurring in 5 -10 % (especially anti-PM/Scl and anti-Scl-70)
49

50. 50

51. Calcinosis cutis, fingers
51

52. Calcinosis cutis: arm (radiograph)
52

53. Raynaud’s phenomenon
Cyanosis of the hands
53

54. Raynaud’s phenomenon: hand (angiogram)
Vasospasm
54

55. Diffuse cutaneous scleroderma
• Raynaud phenomenon followed, within one year, by puffy or
hidebound skin changes
• Truncal and acral skin involvement;
• Tendon friction rubs
• Nailfold capillary pattern typical of scleroderma with dilatation
(early), dilatation and dropout (active), and tortuosity with
dropout (late)
• Early and significant incidence of renal, ILD, diffuse GIT, and
myocardial disease
• Anti-Scl-70 (30 %) and anti-RNA polymerase-I, II, or III (12 - 15%)
antibodies
55

56. Scleroderma: skin induration, hands
56

57. Scleroderma sine scleroderma
• Presentation with pulmonary fibrosis or renal, cardiac,
or GIT disease
• No skin involvement
• Raynaud phenomenon may be present
• ANA may be present (anti-Scl-70, ACA, or anti-RNA
polymerase-I, II, or III)
57

58. Overlap syndromes
• Features of systemic sclerosis that coexist with
those of another autoimmune rheumatic
disease, such as SLE, RA, dermatomyositis,
vasculitis, or Sjögren's syndrome
58

59. Pre-scleroderma
• Raynaud phenomenon
• Nailfold capillary changes (early or active
pattern typical) and
• Evidence of digital ischemia
• Specific circulating autoantibodies -
antitopoisomerase-I (Scl-70), anticentromere
(ACA), or anti-RNA polymerase-I, II, or III or
other hallmark scleroderma reactivity
59

60. Scleroderma Cutaneous Manifest.
• Skin thickening
• Telangectasias
• Digital pitting scars
• Calcium deposition
• Skin ulceration
60

61. Other clinical manifestations
• Musculoskeletal
– Arthralgias and myalgias
– Synovitis, tendonitis
• GI
– Small oral aperture
– Esophageal dysfunction
– Bowel dysmotility
61

62. Cont.
• Pulmonary:
– Fibrosis and inflammation with ILD
• Cardiac
– Myocarditis, pulmonary HTN, arrhythmias
• Renal
– Scleroderma renal crisis, renal failure
62

63. Scleroderma: facial changes, lateral view
Hypopigmented macules are seen
63

64. Scleroderma: mauskopf, facial changes
64

65. Beak-like nose, hypopigmented macules
65

66. The American College of Rheumatology (ACR)
criteria for the classification of systemic sclerosis
• Require one major criterion or two minor criteria
• Major criterion:
Symmetric thickening, tightening, and induration of the
skin of the fingers and the skin that is proximal to the
metacarpophalangeal or metatarsophalangeal joints.
These changes may affect the entire extremity, face,
neck, and trunk
66

67. Minor criteria
• Sclerodactyly
• Digital pitting scars or a loss of substance from the finger
pad
• Bibasilar pulmonary fibrosis
67

68. Scleroderma-like syndromes
• Toxin- or drug-induced scleroderma
– Organic solvents and epoxy resins
– Eosinophilic myalgia syndrome (L-tryptophan)
– Bleomycin
• Vibration injury
• Scleromyxedema
• Eosinophilic fasciitis
• Graft-versus-host disease
68

69. Raynaud’s phenomenon
• Episodic, reversible digital skin color change
– white to blue to red
– well-demarcated
• Due to vasospasm
• Usually cold-induced
• Primary (Raynaud’s disease) and secondary forms
69

70. Causes of secondary Raynaud’s phenomenon
• Connective tissue diseases
– Scleroderma, systemic lupus erythematosus, MCTD,
undifferentiated CTD, Sjogren’s syndrome,
dermatomyositis
• Occlusive arterial disease
– Atherosclerosis, anti-phospholipid antibody syndrome,
Buerger’s disease
• Drugs and toxins
– Beta blockers, vinyl chloride, bleomycin, ergot,
amphetamines, cocaine
70

71. Investigations
The diagnosis is made clinically
• Blood count
• ESR
• Scleroderma associated antibody Scl-70 (topoisomerase 1
antibodies)(30%)
• ANA(90-95%)
• Skin biopsy-T lymphocyte infiltration, fibrosisX-ray of the
hands
• CXR - insensitive
• Chest CT scan - lung fibrosis
• Pulmonary function tests
• ECHO- pericardial effusion,PAH
• Right heart catheterization - PAH
71

72. LAB Finding
• Topoisomerase I (formerly Scl–70) is present in
30% of patients with diffuse disease (absent in
limited disease) and has an increased
association with pulmonary fibrosis
• Anticentromere antibodies are present in
about 40-50% of patients with limited disease
and 10-15% with diffuse disease.
72

73. 73

74. 74

75. Complications
• Most complications are caused by the involvement of
organs other than the skin, but ulcers of the fingertips
and calcinosis are distressing.
• Hard skin immobilizes the joints and leads to
contractures
• Renal, Cardiac, lungs, GIT etc
75

76. Principles of Treatment
• Patient information
• Symptomatic treatment according to presentation
• Physiotherapy to avoid contractures
• Debridement, amputation, correction of contractures
may sometimes be needed
76

77. Managing specific presentations
• Skin thickening - treated with D-penicillamine, interferon-
gamma, mycophenolate mofetil, cyclophosphamide
• Pruritus - treated with moisturizers, H1-blockers, tricyclic
antidepressants
• Raynaud phenomenon - treated with CCBs, Prazosin,
PGE1, aspirin, sildenafil, topical nitrates
• GI symptoms -treated with antacids, H2 blockers, proton
pump inhibitors, smaller meals, and laxatives.
• Pulmonary fibrosing alveolitis - treated with
cyclophosphamide
77

78. • Myositis may be treated cautiously with
steroids, methotrexate, and azathioprine
• Renal crisis episodes are best prevented and
treated with ACE inhibitors
78

79. Prognosis
• Pulmonary hypertension, pulmonary fibrosis and
scleroderma renal crisis are the most frequent
causes of mortality.
• Survival averages 12 years from diagnosis
– The limited cutaneous subset carries a 10-year survival
rate of 71%.
– The diffuse cutaneous subset carries a 10-year survival
rate of 21%.
– Pulmonary hypertension is a major prognostic factor for
survival
79

80. References
• LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic
sclerosis): classification, subsets and pathogenesis. J
Rheumatol 1988; 15:202.
• Laxer RM, Zulian F. Localized scleroderma. Curr Opin
Rheumatol 2006; 18:606.
• Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic
sclerosis sine scleroderma: demographic, clinical, and
serologic features and survival in forty-eight patients. Arthritis
Rheum 2000; 43:444.
• Black CM. Scleroderma--clinical aspects. J Intern Med 1993;
234:115.
80

81. References ...
• Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR
recommendations for the treatment of systemic sclerosis: a
report from the EULAR Scleroderma Trials and Research group
(EUSTAR). Ann Rheum Dis 2009; 68:620.
• van den Hoogen F, Khanna D, Fransen J, et al. 2013
classification criteria for systemic sclerosis: an American
college of rheumatology/European league against
rheumatism collaborative initiative. Ann Rheum Dis 2013;
72:1747.
81

82. Mixed Connective Tissue Disease
(MCTD)
Dr. Basil Tumaini
82

83. Outline
• Introduction
• Clinical features
• Diagnosis
• Treatment
• Prognosis
• References
83

84. Definition
• MCTD is an overlap syndrome including
features of SLE, SSc, and PM
• It is characterized by the presence of high
titers of a distinctive autoantibody, anti-U1-
RNP
• There is a consensus that MCTD is a distinct
DCTD entity
84

85. Clinical features
Presenting features: nonspecific
 frequent fatigue
 myalgias
 arthralgias
 low-grade fevers
Some patients present acutely with: trigeminal
neuropathy, severe polymyositis, acute arthritis,
aseptic meningitis, digital gangrene, acute abdomen
or high fever
85

86. `Characteristic clinical symptoms of MCTD
eventually emerge, including:
 Raynaud phenomenon
 Hand Edema
 Puffy Fingers
 Prominent Synovitis
Overlapping clinical features include
 Inflammatory muscle disease
 Sclerodactyly
86

87. Raynaud Phenomenon
Paroxysmal bilateral cyanosis of the digits due to arterial and
arteriolar contraction; caused by cold or emotion
87

88. Sclerodactyly (Acrosclerosis)
Stiffness and tightness of the skin of the fingers, with atrophy of the soft
tissue and osteoporosis of the distal phalanges of the hands and feet
88

89. 89

90. 90

91. 91

92. Other features
 Cardiac disease: all 3 layers of the heart may
be involved
 Pulmonary involvement: e.g., PE, PAH, ILD,
pleuritic pain, thromboembolic disease
 Renal disease: absence of severe renal disease
is a hallmark of MCTD
 GIT disease: disordered motility,
hemoperitoneum, hematobilia
 CNS disease: trigeminal neuropathy,
headache, sensorineural hearing loss
92

93. Diagnosis of MCTD
• The definitive diagnosis of MCTD is often
complicated by the fact that the overlapping
features tend to occur sequentially
93

94. Clinical features that, taken together, suggest the
presence of MCTD rather than another CTD:
• Raynaud phenomenon and swollen hands or puffy
fingers
• A high titer speckled pattern ANA (usually ≥1280)
• The absence of severe renal and CNS disease
• More severe arthritis, which is sometimes deforming
• The development of PAH, which differentiates MCTD
from both SLE and scleroderma
• Autoantibodies whose fine specificity is anti-U1-RNP,
especially antibodies to the 70 kD protein
94

95. 95

96. Principles of management
• Patient information
• SLE-like features respond to Prednisolone
• SSc-like features are less responsive
• Early routine echo Dx of PAH & Rx (nifedipine,
anticoagulation, IV prostacyclin, glucocorticoids
(+cyclophospamide if necessary) and ACEIs; also
sildenafil
• Severe eruptive skin disease: IVIG
• Hydroxychloroquine
• Methotrexate
96

97. 97

98. 98

99. Prognosis
• Relatively good prognosis
• Overall mortality < with MCTD than in those
with classic SLE
• Causes of death: Progressive PAH and its
cardiac complications, myocarditis,
renovascular hypertension & cerebral
hemorrhage
• Morbidity: quite high
99

100. References
• Bennett RM, O'Connell DJ. Mixed connective tisssue
disease: a clinicopathologic study of 20 cases. Semin
Arthritis Rheum 1980; 10:25.
• Maddison PJ. Overlap syndromes and mixed
connective tissue disease. Curr Opin Rheumatol 1991;
3:995.
• Alarcón-Segovia D, Cardiel MH. Comparison between
3 diagnostic criteria for mixed connective tissue
disease. Study of 593 patients. J Rheumatol 1989;
16:328.
100

101. References ...
• Cappelli S, Bellando Randone S, Martinović D, et al.
"To be or not to be," ten years after: evidence for
mixed connective tissue disease as a distinct entity.
Semin Arthritis Rheum 2012; 41:589.
• Lundberg IE. The prognosis of mixed connective
tissue disease. Rheum Dis Clin North Am 2005;
31:535.
• Kim P, Grossman JM. Treatment of mixed connective
tissue disease. Rheum Dis Clin North Am 2005;
31:549.
• UptoDate
101