Connective tissue disorders involve inflammation of connective tissues leading to skin thickening or scarring, arthritis, and sometimes organ abnormalities. They are considered autoimmune disorders as antibodies form against normal tissues. The main types range from mild skin involvement to severe multi-system disease. Connective tissue disorders include localized forms like discoid lupus erythematosus and systemic forms like systemic lupus erythematosus which can damage multiple organs. Diagnosis involves assessing clinical features, immunological markers, and organ involvement. Treatment depends on disease severity but may include steroids, immunosuppressants, and addressing specific organ complications.

1. Connective Tissue Disorders
Dr. Saad Hashim

2. • The cardinal feature of these conditions is inflammation in
the connective tissues which leads to dermal atrophy or
sclerosis, to arthritis, and sometimes to abnormalities in
other organs.
• Antibodies form against normal tissues and cellular
components; these disorders are therefore classed
a autoimmune.
• The main connective tissue disorders present as a spectrum
ranging from the benign cutaneous variants to severe
multisystem diseases .
Connective Tissue Disorders

3. Classification of connective tissue disease
Localized disease Intermediate type Aggressive multisystem disease
Discoid lupus Subacute lupus Systemic lupus erythematosus
erythematosus
Juvenile dermatomyositis Adult dermatomyositis
Localized scleroderma Diffuse scleroderma Systemic sclerosis
Morphoea CREST syndrome

4. Systemic lupus erythematosus
• Lupus erythematosus (LE) is a good example of such a spectrum, ranging
from the purely cutaneous type (discoid LE), through patterns associated
with some internal problems ( subacute cutaneous LE), to a severe
multisystem disease (systemic lupus erythematosus)
• It is characterized by loss of tolerance to nuclear self antigens, with the
subsequent development of pathogenic autoantibodies which damage
the skin and other organs.
• Variations in the major histocompatibility complex (MHC) are the most
important genetic risk factor for the development of SLE, and a number
of non-MHC genetic variants also play a part.

5. Lupus erythematosus
• Exposure to sunlight and artificial ultraviolet radiation (UVR) may
precipitate the disease or lead to flare ups, probably by exposing
previously hidden nuclear or cytoplasmic antigens to which autoantibodies
are formed. Such autoantibodies to DNA, nuclear proteins and other
normal antigens are typical of LE, and immune complexes formed from
these are deposited in the tissues or found in the serum.
• Hydralazine and procainamide are the most likely drugs to trigger SLE,
while isoniazid, methyldopa, quinidine, minocycline, chlorpromazine and
anti-tumour necrosis factor (anti-TNF) agents precipitate the disease just
occasionally.

6. Lupus erythematosus
Presentation
• Typically, but not always, the onset is acute.
• SLE is an uncommon disorder, affecting women more often than men
• In a ratio of about 8 : 1.
• The classic rash of acute SLE is an erythema of the cheeks and nose in the
rough shape of a butterfly , with facial swelling.
• Blisters occur rarely, and when they do they signify very active systemic
disease.
• Some patients develop widespread discoid or annular papulosquamous
plaques very like those of discoid LE; others, about 20% of patients, have no
skin disease at any stage.
• Other dermatological features include peri-ungual telangiectasia , erythema
over the digits, hair fall especially at the frontal margin of the scalp( lupus hair)
and photosensitivity.
• Ulcers may occur on the palate, tongue or buccal mucosa.

7. Malar rash

8. Lupus lip Lupus hair

9. Course
• The skin changes may be transient, continuous or recurrent
• they correlate well with the activity of the systemic disease.
• Acute SLE may be associated with fever, arthritis, nephritis, polyarteritis,
pleurisy, pneumonitis, pericarditis, myocarditis and involvement of the central
nervous system.
• Internal involvement can be fatal, but about three quarters of patients survive
for 15 years.
• Renal involvement suggests a poorer prognosis.
Complications
• The skin disease may cause scarring or hyperpigmentation, but the main
dangers lie with damage to other organs and the side effects of treatment,
especially systemic treatment.

10. Differential diagnosis
• SLE is a great imitator.
• Its malar rash can be confused with sunburn, polymorphic light
eruption and rosacea , but is more livid in color and swollen in texture.
• The discoid lesions are distinctive, but are also seen in discoid LE and
in subacute cutaneous LE, Occasionally, they look like psoriasis or lichen
planus.
• The hair fall suggests telogen effluvium .
• Plaques on the scalp may cause a scarring alopecia.
• SLE should be suspected when a characteristic rash is combined with
fever, malaise and internal disease .

11. Investigations
• Hematological disorders
- Leukopenia (< 4 × 10 3cells/µL on >1 occasion)
- lymphopenia (< 1500 cells/µL on >1 occasion)
- thrombocytopenia (< 100 × 10 3 cells/µL in the absence of offending
medications)
- hemolytic anemia
• Renal involvement
– Based on presence of proteinuria (>0.5 g/day or 3+ positive on dipstick testing)
or cellular casts (including red blood cells [RBCs], hemoglobin, granular, tubular,
or mixed)or based on the opinion of a rheumatologist or nephrologist

12. Immunological investigation
• Antinuclear antibodies (ANAs)indirect immunoflourescent - Higher titers
generally more specific (>1:160); must be in the absence of medications
associated with drug-induced lupus
• Immunologic phenomena
- Anti dsDNA
- anti-Smith (Sm) antibodies
- antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or
immunoglobulin M [IgM] or lupus anticoagulant)
• Anti (Ro, La antibodies）
• LBT lupus band test (direct immuno-fluorescence )
• Biopsy

13. Criteria
1. Butterfly rash
2. Discoid lupus
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Neurologic: seizure,
psychosis
8. Hematologic cytopenias
such as leukopenia,
lymphopenia, anemia, or
thrombocytopenia)
9. Renal: acute or chronic
renal failure, acute nephritic
disease)
10. Immunologic: anti-DNA,
anti-phospholipid
11. Anti-nuclear antibody
(ANA)
Its importance is suggested by the fact that 4 of the 11 American College of
Rheumatology (ACR) criteria for the diagnosis of SLE are mucocutaneous findings.

14. Treatment
• Systemic steroids are helpful in gaining control of acute exacerbations, but should
not be used for routine use because of the risk of adverse effects.
• Large doses of prednisolone are often needed to achieve control, as assessed by
symptoms, signs, erythrocyte sedimentation rate (ESR), total complement level and
tests of organ function.
• Having gained control with systemic steroids, slower acting immunosuppressive
agents, such as methotrexate, azathioprine , cyclophosphamide and other support
drugs (e.g. antihypertensive therapy or anticonvulsants) can be introduced.
• Antimalarial drugs may help some patients with marked photosensitivity, but the
effectiveness of these is reduced in smokers.
• Sunscreen and appropriate clothing should reduce UV-induced flares.
• Long-term and regular follow up is necessary and the disease should be managed
in conjunction with a rheumatologist.

15. Types of cutaneous lupus
• About 80% of patients with SLE have skin involvement (cutaneous LE) and
it is the first sign of SLE
• Acute
• Subacute
• Chronic (discoid)
• Lupus profundus( lupus panniculitis)

16. Discoid lupus erythematosus
• This is the most common form of LE.
• Patients with discoid LE may have one or two plaques only, or many in
several areas.
• The cause is also unknown but UVR is one factor.
• Plaques show erythema, scaling, follicular plugging (like a nutmeg grater),
scarring and atrophy, telangiectasia, hypopigmentation and a peripheral
zone of hyperpigmentation.
• They are well demarcated and lie mostly on sun-exposed skin of the scalp,
face and ears
• In one variant (chilblain LE) dusky lesions appear on the fingers and toes.

17. Course
The disease may spread relentlessly, but in about half of the cases the disease
goes into remission over the course of several years.
• Scarring is common and hair may be lost permanently if there is scarring in the
scalp.
• Whiteness remains after the inflammation has cleared, and hypopigmentation
is common in dark-skinned people.
• Discoid LE rarely progresses to SLE.
Differential diagnosis
• Psoriasis
• Scarring alopecia
• Lichen planus
• Leishmaniasis, lupus vulgaris

18. Factors distinguishing the different types of SLE
lupus erythematosus (LE) Antinuclear Sun Internal organ
antibodies sensitivity involvement
Systemic LE Often against DNA ++++ +++ ++
Subacute LE Often against SSA+ ++++ +
Discoid LE Often other+/− + −

19. Investigations
• Most patients with discoid LE remain well.
• screening for SLE and internal disease is still worthwhile.
• A skin biopsy is most helpful if taken from an untreated plaque
where appendages are still present
• Direct immunofluorescence shows deposits of IgG, IgM, IgA
and C3 at the basement membrane zone.

20. Treatment of Discoid lupus erythematousus
• Topical corticosteroids ,potent or very potent In this condition, it is justifiable
to use them on the face, as the risk of scarring is worse than that of atrophy.
• Topical calcineurin An alternative to potent topical corticosteroids, This does
not induce atrophy and is thus particularly useful for treating facial lesions.
• Topical retinoids such as tretinoin or tazarotene may be useful.
• Sun avoidance and screens are also important.
• Stubborn and widespread lesions improve in about half of patients treated with
oral antimalarials such as hydroxychloroquine although rarely these cause
irreversible eye damage. The eyes should therefore be tested before and at
intervals during treatment.
• Acitretin has a similar efficacy to hydroxychloroquine, although with more
adverse effects.

21. DLE
DLE

22. Dermatomyositis
• Dermatomyositis is a subset of polymyositis with distinctive skin
changes.
• There are adult and juvenile types
• The cause is unknown but an autoimmune mechanism seems
likely.
• When starting after the age of 40, dermatomyositis may signal
an internal malignancy.
• Presumably, the epitopes of some tumors antigens are so similar
to those of muscle antigens that immune reactions directed
against the tumors cross-react with muscle cells and initiate the
disease in a few adults with internal malignancy.

23. Presentation
• The skin signs are characteristic. Typical patients have a faint lilac discoloration
around their eyes (sometimes called heliotrope because of the colour of the
flower).
• This is associated with malar erythema and edema and, sometimes, less
striking poikiloderma ( pigmentary variation, epidermal atrophy and
telangiectasia) of the neck and presternal area (shawl sign).
• Most patients also develop lilac slightly atrophic scaly papules over the
knuckles of their fingers (Gottron’s papules), streaks of erythema over the
extensor tendons of the hand, periungual telangiectasia and ragged cuticles.
• The skin signs usually appear at the same time as the muscle symptoms but,
occasionally, appear months or even years earlier. Many, but not all, patients
have weakness of proximal muscles.
• Climbing stairs, getting up from chairs and combing the hair become difficult.

24. Gottron’s papules Heliotrope sign

25. Calcinosis cutis

26. Course
• In children the disorder is often self-limiting, but in adults it may be prolonged
and progressive.
• Raynaud’s phenomenon, arthralgia, dysphagia and calcinosis may follow. The
rash may become scaly and, rarely, itchy; eventually that on the light-exposed
areas and overlying involved muscles develops poikiloderma.
• Features of mixed connective disease may develop.
• The presence of calcinosis suggests a good prognosis.
Complications
• Myositis may lead to permanent weakness and immobility, and inflammation to
contractures or cutaneous calcinosis ( calcification occurs in damaged tissue,
usually collagen or elastic tissue).
• Some die from progessive and severe myopathy.

27. Investigations
Up to 25% of adults over the age of 40 with dermatomyositis also have an underlying
malignancy.
Their dermatomyositis coincides with the onset of the tumour and may improve if it is
removed.
In women, the ovaries are a favorite hiding place, but breast, gastrointestinal tract and
lung cancers are also common.
The levels of muscle enzymes such as aldolase and creatinine kinase are often
elevated.
Electromyography (EMG) detects muscle abnormalities, and biopsy of an affected
muscle shows inflammation and destruction.
Magnetic resonance imaging is increasingly used to non-invasively detect
inflammation in clinically involved muscles.
The presence of Jo-1 antibodies in plasma suggests high risk for myositis, arthritis
and interstitial lung disease.

28. Treatment
 Systemic steroids, often in high doses (e.g. prednisolone 60 mg/day for an
average adult, are the cornerstone of treatment and protect the muscles from
destruction. A maintenance regimen may be needed for several years and thus
concomitant osteoporosis prevention with calcium, vitamin D and possibly
bisphosphonates will almost certainly be required.
 Immunosuppressive agents, such as azathioprine or methotrexate , also help
to control the condition and to reduce the high steroid dose.
 Maintenance treatment is adjusted according to clinical response and creatinine
kinase level.
 Some case reports show benefit from intravenous gammaglobulin infusions
or cyclophosphamide, but good clinical trial data are generally lacking in
dermatomyositis treatment.
 Muscle disease usually responds much better than skin disease, but avoidance
of sunlight will prevent UV-induced flares of skin disease.
 Long-term follow up is necessary, although the increased risk of underlying
malignancy reverts to that of the age-matched population 2 years after diagnosis.

29. Systemic sclerosis
• Systemic sclerosis (scleroderma) can affect a number of different
organs, but almost always affects the skin which develops reduced
elasticity, thickening and hardening (sclerosis).
• Vascular damage and altered immune responses are other features
of the disease.
• The pattern of organ involvement, speed of progress and prognosis
separate the disease into two subtypes:
• diffuse cutaneous and localized cutaneous systemic sclerosis .

30. Morphoea
• Morphoea is a localized form of diffuse sclerosis with pale indurated
plaques on the skin but no internal sclerosis.
• Many plaques are surrounded by a violaceous halo.
• Its prognosis is usually good, and the fibrosis slowly clears leaving slight
depression and hyperpigmentation.
• In pansclerotic morphoea, contractures can cause marked disability.
• A rare type may lead to arrest of growth of the underlying bones causing,
for example, facial hemiatrophy or shortening of a limb.
• Little is known about the cause, except that Lyme borreliosis may be
associated with the disease in Europe but not in the Americas.

31. Treatments
• work slowly
• . Phototherapy with UVA or long wavelength UVA (UVA-1)
• topical calcipotriol (calcipotriene)
• topical tacrolimus
• systemic methotrexate, with or without corticosteroids, have
all shown some efficacy in clinical studies.

32. Morphoea En coup de sabre

33. Localized cutaneous systemic sclerosis(CREST syndrome)
• the skin disease is usually confined to the extremities and face, and onset is slow.
• Raynaud’s phenomenon often precedes the skin changes in contrast with dcSSc.
• The fingers become immobile, hard and shiny (sclerodactyly) and abnormal calcium
deposition occurs over pressure points (calcinosis).
• Other vascular features of this form of systemic sclerosis include pulmonary artery
hypertension, digital ulceration and renal crises, but despite this the prognosis is
relatively good.
• LcSSc used to be known as CREST (standing for calcinosis, Raynaud’s phenomenon,
oesophageal dysmotility , sclerodactyly and telangiectasia).
• Telangiectasia is periungual on the fingers and flat, mat-like or rectangular
on the face.

34. Diffuse cutaneous systemic sclerosis
• This form of systemic sclerosis shares some features with lcSSc such as Raynaud
phenomenon and sclerodactyly , but the onset of disease is more rapid, and
Raynaud’s phenomenon occurs concurrently with sclerodactyly.
• Anti- DNA topo I (anti-Scl-70) antibodies are found.
• Skin involvement is more widespread than in lcSSc and as the disease progresses,
sclerosis spreads to the face, scalp and trunk.
• Sclerotic skin can become hypo or hyperpigmented and itchy early in the disease.
Periungual telangiectasia is common.
• The nose becomes beak like, and wrinkles radiate around the mouth.
• Loss of hair follicles and sebaceous glands in affected areas of skin leads to alopecia
and dryness.
• hypertension.

35. Skin signs of diffuse scleroderma.
• Raynaud’s phenomenon (95%)
• Sclerosis (especially hands and fingers)
• Diffuse darkening (hyperpigmentation)
• Pinched nose
• Mask-like face
• Decreased oral aperture
• Square mat telangiectasias
• Thin lips
• Prominent periungual capillaries
• Nail abnormalities (pterygium)
• Calcinosis cutis
• Painful digital ulcers

36. Facial manifestation of systemic sclerosis
• Pinched nose
• Mask-like face
• Decreased oral aperture
• Square mat telangiectasias
• Thin lips

37. Diffuse cutaneous systemic sclerosis
• Most have abnormalities of the gut including dysphagia, oesophagitis,
constipation, diarrhoea and malabsorption.
• Interstitial lung disease leads to dyspnoea; fibrosis of the heart and
pulmonary hypertension to congestive failure.
• The kidneys are involved late, but this has a grave prognosis from
malignant
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.

38. Differential diagnosis
• chilblains
• erythromelalgia
• morphoea
• porphyriacutanea tarda
• mixed connective tissue disease
• eosinophilic fasciitis
• diabetic sclerodactyly
• progeria, scleromyxoedema, amyloidosis or carcinoid syndrome
• Nephrogenic sclerosing dermopathy

39. Investigations
• The diagnosis is made clinically because histological abnormalities are seldom
present until the physical signs are well established.
• Laboratory tests should include a fluorescent antinuclear antibody test and
the evaluation of the heart, kidney, lungs, joints and muscles.
• Barium studies are best avoided as obstruction may follow poor evacuation.
Other contrast media are available.
• X rays of the hands, measurement of muscle enzymes and immunoglobulin
levels, and a blood count, ESR and test for the scleroderma-associated
antibody Scl-70 are also worthwhile.

40. Treatment
• This is unsatisfactory.
• The calcium channel blocker nifedipine or the guanylate cyclase inhibitor
sildenafil may help Raynaud’s phenomenon.
• Systemic steroids ,methotrexate, mycophenolate mofetil, salicylates and
antimalarials are used, but are not of proven value.
• d-penicillamine has many adverse effects, especially on renal function.
• Physiotherapy is helpful
• photopheresis is experimental.
• Recently, there have been promising reports of the efficacy ofUVA-1 (340–400
nm) phototherapy for affected skin in systemic sclerosis.
• Antagonists to endothelin receptors such as bosentan reduce risks from
pulmonary hypertension.