1. CTD objectives Know why CTDs are considered autoimmune diseases
Know what the epidemiology of CTDs implies about their pathophysiology
Understand the concept of disease criteria
Know the criteria for SLE and SSc
Consider the role of immune pathways in autoimmune disease pathogenesis
Review principals of therapy for SLE and PSS
In order to achieve the goals as expressed, reading and studying will also be required. Expertise is not possible in the allotted time, but exposure is appropriate so as to provide a framework for your future learning.

2. Recommended reading Primer on Rheumatic Diseases,
12Ed p and p
Lange Current Medical Dx and TX p
LeRoy EC, Lomeo R: The spectrum of scleroderma. (parts 1 and 2) Hosp Pract 24(1989).
Systemic Lupus Erythematosus. Science & Medicine Jul-Aug, 1999, p
In addition, sections in the abbreviated texts, such as the Lange series of textbooks are particularly helpful, clinically relevant and effective use of your time.

3. Connective Tissue Disease
Definitions
Connective tissue diseases are those syndromes manifest as multiple organ system involvement in which the pathogenesis is heavily dependent on self- directed immune mechanisms
Examples
SLE, MCTD, SS, PSS, polymyositis

4. Connective tissue diseases (CTD) are characterized by specific properties
General systemic features-malaise, fever, weight loss
Evidence for multiple organ system involvement
Musculoskeletal involvement-arthritis, myalgia
Immune alterations-lead to pathologic inflammation
Therapeutic response to immunosuppression
These diseases are grouped together because they are systemic, that is they affect the body as a whole through involvement of multiple organ systems, they require immune activation and in general they share epidemiologic predispositions and a similar response to immunosuppression.

5. 1997 update of the 82 revised criteria for SLE
Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Nonerosive arthritis
Serositis
Renal disorder
Neurologic disorder
Hematologic disorder
Immunologic disorder
Antinuclear antibody(ANA)
Recognize that these are “revised criteria” and realize that they will change further as we increase our understanding of the disease process. Note also, that mucocutaneous (rash and mouth sores), arthritis and the serologic markers account for the lion share of all manifestations. The threshold of proof varies greatly among physicians and patients leading to much disagreement over whether a given patient has SLE. These criteria were not designed to be used explicitly for that purpose, but instead to enrich studies for similarly effected patients.
Must have 4 criteria
Modified from the Primer

6. SLE CRITERIA DEFINITIONS
Malar Rash
Fixed erythema, flat or raised, sparing the nasolabial folds
Discoid Rash
Raised patches, adherent keratotic scaling, perifollicular plugging, Older lesions may cause scaring
Photosensitivity
Skin rash from sunlight

7. SLE criteria definitions
Oral or nasopharyngeal ulcers
Usually painless
Arthritis
Nonerosive, inflammatory in two or more peripheral joints
Serositis
Pleuritis, or pericarditis

8. SLE criteria definitions
Renal disorder
Persistent proteinuria or cellular casts
Neurologic disorder
Seizures or psychosis
Hematologic disorder
Hemolytic anemia, leukopenia (<4,000/mm3)
lymphopenia (<1,500/mm3) or thrombocytopenia (<100, 000/mm3

9. SLE criteria definitions
Immunologic disorder
LE cells or
Antibodies to ds-DNA, Sm, IgM or IgG aCL, false + VDRL
ANA test
Positive

10. Antinuclear antibodies (ANA)
99% of SLE patients
5% of normals
Prevalence is approximately =1/1000 women
Hence- if 1000 women are tested; 51 are ANA positive of which only 1 has SLE
ANA are not “the lupus test”. Many more “normal” people are positive for it than are people with lupus. However, it’s absence speaks strongly against a patient having SLE. It is still unclear as to whether ANAs are part of the pathology or an epiphenomenon caused as a consequence of the true pathology. Serial levels are almost never useful.

11. ANA Pattern associations
A patient’s sera is diluted serially and applied to cells that have been fixed so that they are permeable to proteins. After washing, an anti-human antibody is reacted to the cells, washed and screened for fluorescence patterns. A change of 1 dilution up or down is not considered a change at all. Patterns such as homogeneous, speckled, rim, centromere and nucleolar are usually reported.
This table highlights some of the specific antigens that would result in a given pattern.

12. ANA testing
This table is to show an approximate 1:1 mapping of the pattern of the serology and specific CTDs. In practice, this tends to not be very helpful as variable titers over time and tests with multiple patterns complicate the interpretation.

13. ANA profiles in connective tissue disease
SLE
MCTD
dSSc
CREST
1 Sjogrens RA
ANA
95%
70-90%
60-90%
70%
40-50%
Ds-DNA
60%
neg Sm
30%
RNP
common
rare
Centromere
10-15%
Ro (SS-A)
Neg
La (Ss-B)
15%
This table shows frequency of occurrence of selected serologies in different CTDs. Each is influenced dramatically by the specifics of the population examined. For example, although anti-Sm antibodies are relatively specific for SLE in all populations, anti-Sm is 2.5x more frequently seen in black patients with SLE than in white patients making application of such tables to a specific patient quite difficult.

14. Malar rash of SLE
Classical lupus malar eruption. You should appreciate the quite different appearance on these two individuals. Sparing of the nasal-labial line is helpful when present as is shown on the patient at the right, but clearly is not present on the gentleman at left.

15. Subacute cutaneous lupus
Many other rashes occur in LE including subacute cutaneous lupus (SSLE).
Also, involvement of other systems as shown by the effected glomerulus at right.
Both are a similar size blood vessel under attack by the immune response.

16. Discoid rash

17. SLE-nonerosive arthritis
The key to the arthritis is the absence of significant erosions. Short of those, these hands look very much like those of RA. They clearly have deformity with swan neck formation and ulnar drift.

18. SLE onset by sex and age
This figure highlights the variation in diagnosis based on sex by age. It provides a hint towards the pathogenesis of SLE. What does it imply to you?

19. SLE by race
This table shows data pertaining to race and the diagnosis of SLE. How might these data be misleading? Think about what these numbers would be like in my practice.

20. LE disease triggers Possible Definite Probable Smoke Vinyl chloride
Ultraviolet light
Drugs
Sulfa antibiotics
Probable
Chemicals
Hydralazine
Procainamide
Anti-TNF
Hair dyes
Lipstick
Infections
EBV
Possible
Smoke
Vinyl chloride
Asbestos
Silicone
Foods
Hydrazines
L-Canavanine
Given that an individual is at risk for the development of SLE or another CTD because of their family heritage, age, and/or sex; then what else has to occur in order for the disease to result?
The only well documented trigger is UV light. Many others are considered probable or likely, but remain unproven. Some of these are listed. Patients should be cautioned about their exposure to UV light and steps taken to limit it.

21. Survival by decade Modified from Wallace
This Figure shows some improvement in 5 year survival and a better increase in 10 year survival. What accounts for these increases? Can we expect more?
Modified from Wallace

22. Serious or life-threatening consequences of SLE
One way to address this is to look at what causes serious or life-threatening consequences in SLE patients. This table shows that nephritis, thrombocytopenia and cerebritis are the most frequent causes of serious problems. Other data is beginning to show late deaths tend to be vascular, especially CVA and MI. Hence, treatment needs to be focused at limiting these specific problems. Could the treatments be contributing to the cardiovascular mortality?

23. SLE treatment Modified from Wallace
Thus far, no specific treatment for SLE exists (possible exception of BMT). Instead, we treat specific manifestations. If a patient has arthritis, arthralgias or myalgias, we use NSAIDS. If they have a rash, we use steroids and anti-malarials. As the risks of serious organ damage or death increases, so does the use of higher dose steroids and immunosuppressives.
Most recently DHEA (prasterone) has been added to the armamentarium. It seems to help with fatigue, myalgias and to minimize glucocorticoid dosage.
Modified from Wallace

24. Cytotoxic medications
This is included to give you a starting point towards understanding which medications are used in serious lupus. Look especially at cyclophosphamide as the mainstay of these meds. Note the serious “Side Effects” that need to be weighed against the potential benefits.

25. Preliminary criteria for Scleroderma (PSS or SSc)
Major criteria
Proximal scleroderma
Minor criteria
Sclerodactyly
Digital pitting
Bibasilar pulmonary fibrosis
Scleroderma is an example of a clinically defined syndrome with very simple criteria. Notice, you can be diagnosed if you have scleroderma proximally. Proximal to what? Of course there is some debate on this question, but the MCPs, wrists and elbows are the favored answers.
1 Major or two or more minor must be met.
Modified from the Primer

26. Clinical subsets of scleroderma
After diagnosis, splitters like to divide the patients further into two or more varieties, here shown as lSSc and dSSc. It seems logical to do so, because of the grossly different prognosis associated with these two clinical patterns. Often, patients seem to defy this clear dichotomous separation and drift back and forth between the two types with manifestations of each.

27. Scleroderma antibodies
Again, a number of ANA-associated serologies have been described. They tend to add little to routine care of and diagnosis of scleroderma patients. However, evidence of prognostic differences or of manifestation differences based on particular antibodies is beginning to emerge. If it becomes reliable, it would change their importance. Currently, most patients are screened for ANA, SCL-70 and anti-centromere antibodies as they have the most direct relationship to prognosis.

28. Scleroderma dSSc lSSc
Two classic manifestations-peri-oral fibrosis and telangiectasias. Efforts to quantitate the mouth opening usually count how many fingers can fit between the incisors. The telangiectasias tend to be a favorable prognostic sign and are more typical of but not limited to lSSc.

29. Sclerodactyly of hands
Notice, the the shiny quality of the skin, without hair or wrinkles, the loss of pulp at the end of the fingers, the pits on some PIPs and the flexion contractures of the PIP joints. These contractures can be highlighted further by use of a “prayer sign”.

30. Calcinosis cutis
The white toothpaste like material visible through the skin of this patient is calcification caused as part of scleroderma. It feels firm like bone, but can erode the skin, get super-infected and be a major source of discomfort. Although this represents the “C” in CREST, one can also see it in diffuse scleroderma. The radiograph demonstrates why it feels like bone.

31. Survival of dSSc vs normals
PSS
These survival curves highlights the severe prognosis associated with dSSc patients (here called PSS). These patients have a survival t 1/2 of about 6 years, very similar to severe CHF and many neoplasias.

32. Scleroderma survival-Effect of Lung Disease
No lung dx
UIP
PAH

33. Diseased organ system or event leading to death in
patients with systemic sclerosis (dSSc).
In general, we have been unable to modify the previously shown survival curves. However, several recent developments may change that. For example, ACE inhibitors are very effective for treating renal crisis. As seen in this chart, renal, cardiac and pulmonary causes of death are the most common.

34. Scleroderma lung
The pulmonary disease has recently been shown to be at least somewhat responsive to cytoxan therapy. Secondly, pulmonary hypertension can be improved with anti-endothelin approaches and prostaglandins.

35. dSSc GI Renal
These images are to remind you that scleroderma is a systemic disease, clearly more than skin-deep.
The changes in the kidney are very characteristic and clearly show the vascular pathology of the disease, unlike SLE which has much more involvement of the glomeruli.

36. Treatment of scleroderma renal crisis
As described earlier, ACE inhibitors and likely ARB dramatically alter renal crisis. In fact, many patients who need dialysis because of renal crisis are able to discontinue it if their ACE is continued throughout the event.

37. Treatment of scleroderma
Focus on symptoms
Antibiotics for bowel motility
Gloves for Raynaud's
Treat responsive syndromes
PAH with bosentan, flolan, Rovatio
Renal crisis with ACE inhibitors

38. Summary CTD are multi-system diseases
Immune mechanisms are key to their pathogenesis and therapy
Diagnosis are clinically based using criteria
Treatment is non-specific-aimed instead at specific manifestations
A move toward prevention of key complications like CAD and renal crisis is in progress

39. Case #1
A 23 year old female went hiking at Zion park last week. Now, she presents with rash on her chest and face, arthritis of her right knee and severe chest pain that worsens with deep inspiration or twisting movements of her back. Further, she relates a history of her hands looking as if they had frostbite every time she failed to wear her gloves while skiing last winter.

40. Heliotrope and photosensitivity rash of dermatomyositis
Notice the similarity of these rashes to those of SLE. The picture on the left also shows the heliotrope rash on the eye lids. Like in SLE, these are photosensitive rashes.

41. Case #1
A 23 year old female went hiking at Zion park last week. Now, she presents with rash on her chest and face, arthritis of her right knee and severe chest pain that worsens with deep inspiration or twisting movements of her back. Further, she relates a history of her hands looking as if they had frostbite every time she failed to wear her gloves while skiing last winter.

42. What’s up Doc?
As her physician, you are convinced she has a CTD and feel a diagnostic workup is in order. This should include which of the following tests?
ANA
EMG
Skin biopsy
Muscle biopsy
CXR
Urinalysis
CBC
Head MRI
Be able to explain why each answer was offered, even if it is not correct.