CONNECTIVE TISSUE DISEASES CONNECTIVE TISSUE DISEASES
PROF. IHAB YOUNIS
DISCOID LUPUS ERYTHEMATOSUS (DLE)
Etimology:from Latin lupus = wolf apparently because it "devours" the affected part
ETIOLOGY
•The male to female ratio is 1:2
•May occur at any age but most often occurs in persons aged 20-40 years
•The exact cause is unknown but some factors are associated with DLE
1-Genetic factots: A family history was found in 4% of patients and it occurs in identical twin sisters
2-Exposure to ultraviolet rays:
•Skin lesions clinically and histologically compatible with DLE were induced by UVB and UVA radiation in 42%
of patients with DLE
•It has been suggested that a heat shock protein is induced in the keratinocyte following ultraviolet light exposure
or stress, and this protein may act as a target for T-cell–mediated epidermal cell cytotoxicity
3-Viruses: The finding of antibodies to reovirus RNA in 42% of patients suggests that viruses may have a role in
DLE
4-Other factors: a history of
•A history of trauma (including X rays, diathermy, chemical burns) was given by 11% of patients
•A history of stress was given by 12% of patients
•A history of infection (including herpes zoster) was given by 3% of patients
•Drug intake (including isoniazid, penicillamine,griseofulvin, dapsone) was reported by some patients
•Exacerbation of the disease in summer was reported by 50 % of patients. Also premenstrual exacerbation was
reported by 13 % of patients
CLINICALLY
•DLE predominantly affects the cheeks, nose and ears, but sometimes involves the upper back, V area of the neck,
backs of hands and scalp. The lips and oral mucosa may be affectied, causing ulcers and scaling. These lesions may
predispose to Squamous cell carcinoma
•14% of patients have Raynaud’s phenomenon and 22% had chilblains
•The primary lesion is an erythematous papule or plaque
•There is adherent scale in many cases. The undersurface of these scales shows horny plugs which have occupied
dilated pilosebaceous canals
•As the lesion progresses, pigmentary changes may develop, with hypopig-mentation in the central area and
hyperpigmentation at the active border
•As lesions age, dilation of follicular openings occurs with a keratinous plug, termed follicular plugging or
patulous follicles
•Palms and soles may be affected in less than 2% of patients
•Mucosal surfaces may be affected by lesions identical to DLE of the skin or by lesions that may simulate lichen
planus
•Resolution of the active lesion results in atrophy and scarring
•If the hair follicles are involved, they are first plugged with adherent scale and then bald areas can develop. If the
follicles are destroyed, cicatricial alopecia will occur
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•Malignant degeneration of chronic lesions is possible, although rare, leading to nonmelanoma skin cancer
•Lichen planus-like lesions may be part of an overlap between LE and lichen planus or may occur as a result of
antimalarial therapy
•Patients may manifest any symptom of SLE; therefore, the history should include an assessment for symptoms of
pleuritis, pericarditis, neurologic involvement, and renal involvement
Types
1- Hypertrophic LE: thickened and warty lesions resembling warts occur
2-Tumid LE:the tissues are swollen, warm and tense
3-Annular atrophic plaques:The centre of the plaques is depressed and sclerotic
4- Disseminated DLE:Lesions occur in a widespread pattern
5-LE panniculitis (profundus) : nodular lesions are of varying size. They are usually firm, rubbery, sharply
defined and persistent.Healing usually leads to the development of depressed areas
6-Chilblains LE:chilblain lesions occur some years after DLE lesions. When DLE lesions remit with treatment,
the chilblains persist
HISTOPATHOLOGY
•Vacuolar alteration of the basal cell layer
•Hyperkeratosis & atrophy of the epidermis
•Follicular plugging
•Hyalinization&edema in the connective tissue occurring immediately below the epidermis
•Lymphocytic inflammatory cell infiltrate in a perivascular, periappendiceal, and subepidermal location
INVESTIGATIONS
•Serologic testing is as follows:
•About 20%of patients manifest a positive antinuclear antibody (ANA) when tested with human substratesAnti-Ro
(SS-A) autoantibodies are present in approximately 1-3% of patients.
•Less than 5 % of patients test positive for Antinative DNA (double-stranded or nDNA) or anti-Sm antibodies
which usually usually reflects SLE
•The following may be present in some patients:
- Cytopenias
- Elevated sedimentation rate
- Rheumatoid factor
- Complement levels may be depressed
- Proteinuria
•Deposition of IgG and/or complement at the dermal-epidermal junction occurs in 90% of patients. Tissue may be
examined from skin lesions or normal skin
•This test is neither sensitive nor specific and has been replaced by advances in serologic testing
TREATMENT
1-Generakl measures:
•Therapy begins with sun-protective measures, including sunscreens, protective clothing, and behavior alteration
•Cosmetic measures, such as cover-up makeup (Covermark ) or wigs, may be suggested for appropriately selected
patients
2-Local therapy:
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•Topical corticosteroids are selected for the type of lesion under treatment and for the site of involvement. For
example, lotions or foams are preferred for the scalp, weaker agents are used on the face, and superpotent agents
are used for hyper-trophic lesions
•Intralesional injection of corticosteroids is useful in resistant cases. The total dose of the injections at each clinic
visit must be calculated to avoid systemic steroid toxicity
•Among other local measures, cryotherapy, surgical excision, painting small lesions with trichloracetic acid may
be helpful
•The carbon dioxide laser, and both the pulsed-dye and argon lasers may be valuable for telangiectatic LE
3-Systemic therapy:
•Severe cases need oral therapy in addition to local and general measures
•For patients with severe, extensive or scarring disease, particularly affecting the scalp, oral prednisolone is often
the most helpful. A dosage of 0.5 mg/kg, rapidly tapered over 6 weeks, is quickly effective, minimizes scarring,
and allows the slower acting agents such as antimalarials to work
•In a small number of patients resistant to other maintenance therapy systemic steroids should be continued with
bone protection with bi-phosphonates or related drugs to avoid osteoporosis
•In most cases first-line oral treatment should be with one of the antimalarials e.g. hydroxychloroquine, initially at
200 mg twice daily, reducing to 200 mg/day once a response is achieved. Chloroquine sulphate is equally effective,
usually at the same dose but it is more likely to produce eye side effects as corneal deposits
•Mepacrine is also useful, and is safe from an ophthalmological point of view, but it is often reserved for later use
(because of skin pigmentation). It may be used alone, or as part of a combination of antimalarials, which may be
more effective than the equivalent amount of each drug given individually
•The response to therapy with antimalarials varies; usually, the more tumid, less scaly lesions responding more
rapidly than chronic, atrophic and scarring lesions
•Most patients who are going to respond to antimalarials usually do so within 6 weeks.
•The occurrence of side effects with one agent does not necessarily mean that they will occur with another
antimalarial, so it is always worth trying an alternative drug
•Taking an ophthalmological history and arranging for an examination by an optician before treatment in any
patient with symptoms not corrected by spectacles may help in avoidance of the ocular manifestations.
•Approximately 60–75% of all patients are helped by antimalarials
•Cigarette smoking reduces the efficacy of treatment with antimalarials, probably by modifying metabolism
•Of those who respond, approximately 50% relapse within 6 months of stopping treatment, and repeated courses of
therapy are usually required. The continuation of antimalarials after clearance does not prevent relapses
•Nevertheless, over the course of several years, most cases treated with intermittent oral antimalarials and topical
corticosteroids tend to improve, and some clear completely
•For cases not responding to topical steroids, antimalarials and sunscreens, oral thalidomide (100 mg/day)
produced response rates of 80–90%, but when used as second-line treatment the response rate is nearer 50% Short
courses are preferable because of the risk of polyneuropathy and the teratogenic effects
•The prescription of thalidomide is tightly regulated, with prescribers, dispensers and patients all having to be
registered in a pregnancy prevention programme: patients are allowed only monthly amounts of drug,and all
potentially fertile women should be using double contraception and require monthly pregnancy tests
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
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ETIOLOGY
•SLE is a disorder in which the interplay between host factors (susceptibility genes, hormonal milieu, etc.) and
environmental factors (ultraviolet radiation, viruses, drugs) leads to loss of self-tolerance, and induction of
autoimmunity. This is followed by activation and expansion of the immune system, and eventuates in immunologic
injury
I-HOST FACTORS
1-SUSCEPTIBILITY GENES
•More than 10 gene loci are known to increase the risk of SLE
•Genetic predisposition is found in 25% of monozygotic twins versus 2% in dizygotic twins
•Studies of HLA reveal that HLA-A1, B8, and DR3 and deficiency of some complement types are more common
in SLE patients than controls
2-SEX HORMONES
•The female-male ratio of 9:1 and the use of exogenous hormones has been associated with onset and flares,
suggesting a role for hormonal factors in the pathogenesis of the disease
•SLE is frequent in women of childbearing age, but it does not have an age predilection in males
•High levels of estrogen and progesterone promote humoral autoreactivity. Patients with lupus metabolize
estrogens differently and have up to a 20-fold increase in the fraction of high-potency to low-potency estrogens
when compared with healthy controls
•High levels of estrogen have been shown to cause patients with SLE to have an increase in (1) the number of selfreactive lymphocytes that bypass developmental deletion, (2) an increase in CD4/CD8 ratio (favoring humoral
responsiveness)
II-ENVIROMENTAL FACTORS
1-ULTRAVIOLET RADIATION
•UV radiation (UVR) is probably the most important environmental factor in the induction phase of SLE
•UV light likely leads to self-immunity and loss of tolerance because it causes increase in apoptosis of
keratinocytes leading to the presence of antigens so lymphocytes begin targeting normally protected intracellular
antigens
2-TOBACCO EXPOSURE
•Smokers are at a greater risk of developing SLE than are nonsmokers
•This fact may be related to lipogenic aromatic amines, which are contained in tobacco smoke
3-DRUGS
•Numerous drugs have been implicated in inducing some features of SLE(See DLE)
•These drugs induce T-cell DNA hypomethylation causing altered repair of DNA
4-Viruses
•The role of infectious etiologies such as Epstein-Barr virus or cytomegalovirus is evidenced by the fact that
Infection is more common in SLE patients than in normal persons
•Microbial superantigens (antigens which cause non-specific activation of T-cells resulting in polyclonal T cell
activation and massive cytokine releasemay) stimulate abnormal T- and B-cell interactions, resulting in the state of
autoimmunity
III-AUTOIMMUNITY
1.B-CELLS
•Show abnormal maturation and activation
2.T-LYMPHOCYTES show
•Decreased peripheral T lymphocytes
•T-cell hyperactivity
•Decrease in number and function of T suppressor cells
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3. ANTILYMPHOCYTE ANTIBODY
•Lymphocytotoxic antibodies
are present in sera of 80% of SLE patients
4.ANTINUCLEAR ANTIBODIES against:
• Nuclear membrane targets
•Chromatin targets
•Ribonucleoprotein targets
Relationship of genetic, environmental factors and autoimmunity
•Genetic factors might allow virus replication in the thymus and in T cells, inducing damage to these cells leading
to defective cellular immunity
•Normally, changes in thymus lymphoid cells, auto-antibody formation from hyperactive B-cells and the lack of Tcell suppression are prevented by normal defense mechanisms. But these mecha-nisms may be impaired by
infections, drugs, UV radiation& stress, thus precipitating the disease
CLINICALLY
1-Constitutional symptoms
•Nonspecific fatigue (the most common constitutional symptom) , fever, arthralgia, and weight changes are the
most common symptoms in new cases or recurrent active SLE flares
2-Musculoskeletal symptoms
•Involvement of the joints occurs in approximately 90% of patients
•Arthralgia, myalgia, and frank arthritis may involve the small joints of the hands, wrists, and knees. In contrast to
rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling
3-Dermatological symptoms
A- Malar rash, which is characterized by an erythematous rash over the cheeks and nasal bridge (butterfly rash)
sparing the nasolabial folds. It lasts from days to weeks & is occasionally painful or pruritic
•B- Photosensitivity: All humans are photosensitive, developing reddening of the skin if exposed to sufficient
ultraviolet radiation (UVR). Therefore photosensitivity is defined in clinical practice as an abnormal cutaneous
response to UVR
•C-Discoid rash similar to DLE. It may be a part of SLE or may represent DLE without organ involvement,
which is a separate diagnostic entity
•D-Alopecia: occurs in 50% of patients. It takes the form of diffuse loss of hair with a reddish scalp. The hair is
usually coarse, dry and fragile, especially on the frontal margin. This leads to an unruly appearance with short,
broken-off hair(lupus hair). The hair recovers as the disease becomes inactive
•E-Other cutaneous manifestations related to but not specific to SLE include Raynaud phenomenon, livedo
reticularis, panniculitis (lupus profundus), bullous lesions, vasculitic purpura, telangiectasias, and urticaria
•Mucous membranes affection occurs in 26% of cases as shallow and sometimes painful ulcers, with a dirty yellow
base and surrounding reddish halo
4-Renal features
•The kidney is the most commonly involved visceral organ in SLE
•Although only approximately 50% of patients with SLE develop clinically evident renal disease, biopsy studies
demonstrate some degree of renal involvement in almost all patients
•Glomerular disease usually develops within the first few years of SLE onset and is usually asymptomatic
•Acute or chronic renal failure may cause symptoms related to uremia and fluid overload
•Acute nephritic disease may manifest as hypertension and hematuria
•Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia
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5- Neuropsychiatric features
•Only seizure and psychosis are included among neurological features of the disease
•Psychosis may manifest as paranoia or hallucinations. Delirium represents a spectrum of fluctuating altered
consciousness characteristic of SLE
6- Pulmonary features
•Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute
pulmonary involvement in SLE
7- Gastrointestinal features
•GIT symptoms are common. Abdominal pain in SLE is significant because it may be directly related to active
lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. Nausea and dyspepsia are
common symptoms
•Liver lesions including granulomatous hepatitis, chronic active hepatitis & cirrhosis occur in one third of patients
8- Cardiac features
•Pericarditis that manifests as chest pain is the most common cardiac manifestation of SLE, manifesting as
positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in SLE with
heart failure symptomatology
9-Hematologic features
•A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest
SLE
CRITERIA FOR DIAGNOSIS
•The American College of Rheumatology put 11 criteria that summarize features necessary to diagnose SLE
•The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE
•Patients with SLE may present with any combination of clinical features and serologic evidence
•The first letter of each criterion is grouped into the sentence: "SOAP BRAIN MD"
1. Serositis—pleurisy or pericarditis
2.Oral ulcers
3.Arthritis - Nonerosive
4. Photosensitivity
5. Blood disorder—hemolytic anemia or leukopenia (<4000/mm) or lymphopenia (<1500/mm) or
thrombocytopenia (<100 000/mm
6. Renal disorder—persistent proteinuria (>0.5 g/day) or cellular casts
7. Antinuclear antibodies
8. Immunological disorder:LE cells or anti-DNA antibody or anti-Sm antibody or false+ve serology for syphilis
(longer than 6 months)
9. Neurological disorder:seizures or psychosis
10. Malar rash
11.Discoid rash
HISTOPATHOLOGY
•Epidermal changes are similar to DLE
•The dermal tissues may be edematous, with dilatation of the superficial vessels and perivascular lymphocytic
infiltration
LABORTATORY INVESTIGATIONS
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I-Tests for antinuclear antibodies(ANA)
•They superseded the LE test
•Antinuclear antibodies are a unique group of autoantibodies that have the ability to attack structures in the nucleus
of cells
•One or more antinuclear antibodies can be detected by fluorescent antibody techniques in over 80% of cases
•Patient’s serum is added to human cells on a slide
•A second antibody, tagged with a fluorescent dye, is added to the mix of patient's serum and cells on the slide.
The second (fluorescent) antibody attaches to the serum antibodies and cells which have bound together. When
viewed under an ultraviolet microscope, antinuclear antibodies appear as fluorescent cells in +ve cases
Four staining patterns can be demonstrated, representing four systems of antinuclear antibodies:
1. Homogeneous pattern, the nuclei are stained all over. It is the most common presentation
2. Speckled pattern : minute points of fluorescence are scattered all over the nucleus
3. Nucleolar pattern : uniform staining of each nucleolus
4. Peripheral or membranous pattern : staining occurs at the periphery of the nucleus
II-Other antibodies
1- antihistone antibodies: They are associated with a lower incidence of renal and CNS disease, alopecia, anemia
and decreased complement
2- Anti-Sm antibody:appears to occur in patients with renal disease, CNS disease and vasculitis
3- Anti-RNP antibodies: Its titers correlate with disease activity
4-Anti-Ro antibody occurs in patients who have an increased tendency to photosensitivity and renal disease
5-Anti-La, an antibody to RNA polymerase
III-Other laboratory tests :
1-Inflammatory markers: Levels of ESR or C-reactive protein (CRP), may be elevated in any inflammatory
condition, including SLE
2-Complement C3&C4 levels: Are often depressed in active SLE because of consumption by immune
3-A CBC count may help to screen for leukopenia, lymphopenia, anemia, and thrombocytopenia
4-Urinalysis and creatinine studies may be useful to screen for kidney disease
5-Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or
(NSAIDS)
IV-Pocedures
•Imaging Studies: e.g. x-ray on joints and chest and MRI brain
•Lumbar puncture may be performed to exclude infection with fever or neurologic symptoms
•Renal biopsy is used to identify the specific type of glomerulonephritis
TREATMENT
I-GENERAL MEASURES
•The patient must have bed rest, avoid sun exposure and stress
II-GLUCOCORTICOIDS
•In acute cases prednisolone(Hostacorten H) is given as a single morning dose of up to 60 mg/day
•A single morning dose produces fewer side effects and does not impair the therapeutic response
•Once the condition appears to be under control, the dosage may be reduced gradually, until a maintenance dosage
of approximately 5–15 mg/day is reached
•Antimalarials are less useful than in DLE, but may allow the dosage of steroids to be reduced
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•It is important to assess the patient’s progress by their general well-being and relief of symptoms, rather than by
strict attention to laboratory abnormalities
•The titer of antinuclear antibodies often persists unchanged despite clinical remission. Anti-DNA antibody and
serum complement levels may be helpful in predicting exacerbations
•Pulse therapy with methylprednisolone 1 g given intravenously in 500 ml normal saline over 4 h on 3 successive
days to in-patients may be helpful in individuals who are not controlled by oral prednisolone and
immunosuppressives
•Given monthly it may prevent deterioration in renal function in patients with nephritis
III-CYTOTOXIC DRUGS
•The role of azathioprine is accepted, but some studies indicate that azathioprine adds nothing to high-dose
prednisolone treatment in mild or moderate renal disease
•Pulsed therapy with cyclophosphamide may be useful for renal disease
•Methotrexate 7.5 mg/week has improved steroid-resistant patients and 10–20 mg/week is useful for
mucocutaneous lesions
IV-OTHER DRUGS
•Ciclosporin has been used in resistant cases in a dosage of 3–5 mg/kg
•Mycophenolate mofetil is increasingly
useful when used for non-renal SLE as a modifier of B cell function
•Rituximab, an antibody targeting the CD20 marker antigen of B cell precursors, has been valuable when
conventional therapy has failed
V- Plasmapheresis
•Plasmapheresis of 2 L/day for 3–4 days each week over a period of 2–3 weeks may be helpful in life-threatening
complications such as fulminating vasculitis or CNS disease with a high level of immune complexes, in patients
whose condition is deteriorating despite other therapy, but controlled trials have not been convincing
VI-UVA EXPOSURE
•Although UV light can exacerbate SLE, it has been found in a new controlled trial that exposure to UVA-1 (340–
400 mm) at a dosage of 60 kJ/m2 three times weekly reduced disease activity, reduced the need for medication and
decreased antibody levels
SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS(SCLE)
ETIOLOGY
•Antibodies to the Ro/SS-A antigen are an almost universal finding in this subset of lupus
•The SSA/Ro antigens are nuclear and cytoplasmic polypeptides which serve as autoantigens in SLE
•Ultraviolet light induces the synthesis of this antigen
•Anti-Ro/SS-A antibodies occur in approximately 80% and antinuclear antibodies are found in approximately 60%
of patients. Anticardiolipin antibodies occur in 16%
•There is an association betwee SCLE with HLA-A1, B8, DR3, DQ2, DRw2and C4 null haplotype
•A number of drugs (e.g. Thiazide diuretics, Griseofulvin,Terbinafine& Calcium channel blockers) have been
reported to precipitate or exacerbate SCLE
CLINICALLY
•Lesions usually occur around the neck, on the trunk and arms
•Follicular plugging and hyperkeratosis are not prominent, and the lesions resolve leaving grey-white
hypopigmentation and telangiectases
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•The pigmentary changes usually resolve completely
•patients with SCLE, have either non-scarring papulosquamous(two-thirds) or annular polycyclic (one-third)
lesions
•Diffuse non-scarring alopecia and photosensitivity occur in approximately half of patients
•Other features include mouth ulceration (especially of the palate), reticular livedo, and Raynaud’s phenomenon
•Approximately half of patients fulfil the criteria for SLE of the American Rheumatism Association
HISTOPATHOLOGY
It is similar to DLE, but SCLE shows:
•Less prominent hyperkeratosis and inflammatory infiltrate
•Severe hydropic degeneration
•Colloid bodies in the lower epidermis and papillary dermis are common
•Edema of the dermis is more pronounced
•Common extravasation of RBCs & dermal fibrinoid deposits
TREATMENT
•The condition in most patients is controlled by sunscreens, topical or intralesional steroids or the macrolides
pimecrolimus and tacrolimus
•In those not responding to these agents, antimalarial drugs are often helpful
•Patients not responding to antimalarials may respond to oral corticosteroids or methylprednisolone, etretinate,
acitretin , isotretinoin, dapsone, oral, intravenous and subcutaneous methotrexate, thalidomide, UVA, IFN-α,
mycophenolate mofetil, intravenous immunoglobulin, etanercept and efalizumab
DERMATOMYOSITIS
ETIOLOGY
•The incidence has been estimated at 5.5 cases per million people, and the incidence is apparently increasing
•Male:Female ratio 1:2
•Peak age of onset is approximately 50 years, and, in children, 5-10 years
•The cause of is unknown; but the following factors have been implicated:
•A genetic component: It may be linked to certain human leukocyte antigen (HLA) types (eg, DR3, DR5, DR7)
•Immunological abnormalities are common. Patients frequently have circulating autoantibodies. Abnormal T-cell
activity may be involved in the pathogenesis of both the skin and the muscle disease
•Autoantibodies to nuclear antigens (ANA) and cytoplasmic antigens may be present. Although their presence may
help to define subtypes of dermatomyositis & polymyositis, their role in pathogenesis is uncertain
•Infectious agents, including viruses (eg, coxsackievirus, parvovirus,echovirus, HIV) andToxoplasma and Borrelia
species, have been suggested as possible triggers of dermatomyositis
•Some drugs may trigger the disease including penicillamine, statin drugs, quinidine, and phenylbutazone
Relationship to malignancy
•The incidence of carcinoma in association with dermatomyositis varies from 15 to 34%
•Dermatomyositis precedes the neoplasm in 40%,both conditions may occur together (26%) or the neoplasm may
occur first (34%)
•The primary tumor most commonly occurs in the lung, breast, female genital tract, stomach, rectum, kidney or
testis
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CLINICALLY
•In 40% of patients, the skin disease is the sole manifestation at onset. Muscle disease may occur concurrently,
may precede the skin disease, or may follow the skin disease by weeks to years
•The heliotrope skin rash is pathognomic to dermatomyositis
•It is noticed on exposed surfaces&is often pruritic, and intense pruritus may disturb sleep patterns
•The heliotrope rash consists of a violaceous-to-dusky erythematous rash with or without edema in a symmetrical
distribution involving periorbital skin. Sometimes, this sign is subtle and may involve only a mild discoloration
along the eyelid margin
•The Gottron papules are another characteristic sign of dermatomyositis
•They are found over the finger joints but may also be found overlying the elbows, knees, and/or feet
•The lesions consist of slightly elevated violaceous papules & plaques. A slight scale and, occasionally, a
thick psoriasiform scale may be present
•Nailfold changes consist of periungual telangiectases and/or a hypertrophy of the cuticle
•Periungual telangiectases may be apparent clinically or may be visible only on capillary microscopy
•Dermatomyositis is often associated with a poikiloderma in exposed skin, such as the V-shaped area over the
anterior neck and upper chest
•Facial erythema may also occur in dermatomyositis
•Scalp involvement is relatively common and manifests as an erythematous-to-violaceous psoriasiform dermatitis.
Clinical distinction from seborrheic dermatitis or psoriasis is occasionally difficult
•A diffuse alopecia with a scaly scalp dermatosis is common in patients with dermatomyositis
•Muscle disease affects the extensor muscles of the arms more than the flexors
•Muscle tenderness is a variable finding
•Affected patients may have difficulty rising from a chair or squatting and raising themselves from this position
•The muscle involvement is not uniform, and histological examination of biopsy material may be negative.
Biopsies should be taken from a muscle that is clinically weak, or identified as abnormal on MRI scanning
•Calcinosis of the skin or muscle is unusual in adults but may occur in as many as 40% of children or adolescents
•Calcinosis cutis manifests as firm, yellow- or flesh-colored nodules, often over bony prominences
PROGNOSIS
•Approximately 50% of patients seem to be responsive to therapy
•Malignancy is a significant cause of death
•The overall mortality is approximately one-quarter
•Calcinosis is a good prognostic feature
•Death usually occurs from respiratory infection, cardiac failure, malnutrition due to difficulty in swallowing,
carcinoma, or from the side effects of steroid therapy
PATHOLOGY
•The histological appearance of the skin depends on the stage of the disease
•In acute dermatomyositis, the changes resemble those of subacute LE, although the dermal edema may be more
extensive and involve all layers of the dermis
•Mucin deposits commonly occur in the dermis
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•In the later stages, the collagen of the dermis may show thickening, homogenization and sclerosis, with thickening
of the walls of cutaneous blood vessels. The epidermis becomes atrophic, with flattening of the rete ridges, and the
basal layer may show an increase in pigment. At this stage, the appearance can be similar to that of scleroderma
•On direct immunofluorescence, IgM, IgG and C3 may be found at the dermal–epidermal junction in 50% of cases
•The subcutaneous fat may show mucoid degeneration and lymphocytic infiltration, or sclerosis and calcification
•Histologically, in the early stages, the muscle fibres show loss of transverse striation, hyalinization of the
sarcoplasm and an increase in sarcolemmal nuclei . Later, the fibres fragment and show granular and vacuolar
degeneration, and basophilic staining with histiocytic phagocytosis
•There is variable cellular infiltration, mainly of lymphocytes, but also occasional plasma cells and macrophages
•The blood vessels in the muscles may show eosinophilic intimal thickening
•Later still, the affected muscle fibres become atrophied and sclerosed
INVESTIGATIONS
1-Muscle enzymes
•The most sensitive/specific muscle enzyme is elevated creatine phosphokinase (CPK), but other enzyme muscles
e.g. aldolase may also yield abnormal results
2-Autoantibodies
–A positive ANA finding is common
– Anti–Mi-2 antibodies are highly specific but lack sensitivity because only 25% of the patients demonstrate them
3-Imaging procedures
•MRI may be useful in assessing for the presence of an inflammatory myopathy in patients without weakness, in
differentiating steroid myopathy from continued inflammation and in selecting a muscle biopsy site
•CT scanning is useful in the evaluation of potential malignancy that might be associated with inflammatory
myopathy
4-Muscle biopsy
•Open or needle biopsy may enhance the clinician's ability to diagnose dermatomyositis
•The biopsy results may be useful in differentiating steroid myopathy from active inflammatory myopathy when
patients have been on corticosteroid therapy but are still weak
5-Investigations of associated malignancy
•Clinical examination (including the breasts, pelvis and rectum)
•Blood count and biochemistry
•Radiography of the chest
•Abdominal ultrasound
•Examination of the stools for occult blood
•Tumor specific markers including PSA, CEA etc.
TREATMENT
•Rest is essential in acute cases
1-Corticosteroids
•Corticosteroids are required in almost all cases, the dosage depending upon the degree of activity
•Initial dosage of as much as 60 mg/day prednisolone may be required. This dosage should be gradually reduced as
the patient clinically improves and the biochemical markers improve
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•A maintenance dosage of 5 -15 mg/day may be required for many months, or even years, and it is important to
balance the maximum therapeutic effect against the presence of side effects
•If the clinical signs and serum CPK level are not improving sufficiently quickly, bolus infusions of
methylprednisolone (1 g on 2–3 successive days) may be tried and are often a good alternative to a high-dose oral
regimen
•Occasionally, weakness may arise from corticosteroid myopathy, and may be difficult to distinguish from an
exacerbation of the disease. Serum enzymes are normal, but the 24-h urinary creatine excretion is raised
2-Immunosupressives
•Oral azathioprine (1.5–3 mg/kg/day in divided doses) as a steroidsparingagent or oral methotrexate in a small
weekly dosage (7.5–15 mg) may be used to suppress disease activity
3- Patients not responding to prednisolone and immunosuppressives may be helped by the addition of ciclosporin 5
mg/kg/day or by plasma exchange
•Cyclophosphamide(Endoxan) 100 mg/day, or as pulsed intravenous therapy, is used in severe cases
4-Biologics
•The biological agents infliximab (directed against tumor necrosis factor) and more usefully rituximab (directed
against the CD20 molecule on B lymphocyte precursors), have been used with success
5-Topical therapy
•If the rash persists while muscle activity improves, a topical steroid or a topical calcineurin inhibitor may be of
value
6-Physiotherapy plays a considerable part in preventing contractures, and careful splinting may also be required
SCLERODERMA
1-LOCALIZED MORPHEA
ETIOLOGY
•The incidence of morphea has been estimated as approximately 25 cases per million population per year
• Women are affected approximately 3 times as often as men
•Two thirds of linear morphea cases occur before age 18 years. Other morphea subtypes have a peak incidence in
the third and fourth decades of life
•The cause of morphea is unknown
•An autoimmune mechanism is suggested by an increased frequency of autoantibody formation and a higher
prevalence of personal and familial autoimmune disease in affected patients
•Morphea can occur at the site of trauma e.g previous radiotherapy
•Infection :Borrelia burgdorferi is suspected to be a possible etiologic agent for morphea
CLINICALLY
I-PLAQUE TYPE
•It is the most common type
•The lesions are, indurated plaques that range from 1- 20 cm
•Lesions are single or multiple
•They often begin as oval-round erythematous to violaceous patches
•In active phases of the disease, a lilac ring may surround the indurated region
•With disease progression, sclerosis develops centrally as the lesions undergo peripheral expansion.
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•Over a period of months to years, the surface becomes smooth, shiny, and ivory in color over time, with loss of
hair follicles and sweat glands
•Hyperpigmentation often ensues as lesions evolve and eventually involute
•Plaque-type morphea is more common on the trunk (especially the lower aspect) than on the extremities, and the
face is usually spared
II-GUTTATE TYPE: The lesions are similar to, but smaller and more numerous than, plaque lesions
III-BULLOUS TYPE: Subepidermal bullae develop overlying plaque-type
VI-DEEP MORPHEA (MORPHEA PROFUNDS,SUBCUTANOUS MORPHEA):
•There are ill-defined, bound-down, sclerotic plaques with a "cobblestone“ appearance
•Lesions are frequently hyperpigmented, but, because of the deeper level of inflammation, theylack the other
color changes typical of plaque-type morphea
•Eosinophilic fasciitis is a variant of deep morphea involving primarily the fascia and is characterized by an acute
onset of symmetric pain and edema of the extremities or trunk, followed by progressive induration with an
"cobblestone“ appearance similar to deep morphea
VI-LINEAR MORPHEA:
•It is a deep morphea , involving the deep dermis, subcutaneous fat, muscle, bone, and even underlying meninges
and brain
•Linear morphea most often occurs on the lower extremities, followed in frequency by the upper extremities,
frontal portion of the head, and anterior trunk
•Frontoparietal linear morphea, called en coup de sabre(a stroke from a sword), is characterized by a linear,
atrophic depression affecting the frontoparietal aspect of the face and scalp
• Scalp involvement results in scarring alopecia
• Loss of eyebrows and eyelashes can also occur in this variant
•Progressive hemifacial atrophy is thought to represent a severe, segmental form of craniofacial linear morphea.
Unlike en coup de sabre, the primary abnormality occurs in the subcutaneous fat, muscle, and bone, although the
skin is typically not indurated or bound down
HISTOPATHOLOGY
•The epidermis may be normal, or flattened and atrophic with loss of the rete ridges
•At first the dermis is edematous, with swelling and degeneration of the collagen fibrils, which become
homogeneous and eosinophilic
•There may be a scanty perivascular lymphocytic infiltrate
•Later, the dermis is markedly thickened, with dense collagen and relatively few recognizable fibroblasts. The
elastic tissue is reduced
•The dermal appendages and dermal and subcutaneous fat are progressively lost
INVESTIGATIONS
•Laboratory tests have a limited role in the evaluation of patients with morphea
•Autoantibodies are commonly present in all types of morphea. Their clinical and prognostic significance remains
unclear e.g. Rheumatoid factor is positive in 15-60% of patients and Antinuclear antibodies are present in
approximately 46-80% of patients
TREATMENT
•Plaque-type morphea often undergoes gradual spontaneous resolution over a 3-5 years
1-Topical theary:
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•Treatment of active lesions with superpotent topical or intralesional corticosteroids may help reduce inflammation
and prevent progression
•Therapy with topical calcipotriene may also be beneficial, especially when nightly occlusion is used to increase
penetration
2-Systemic therapy:
•Successful treatment of severe and/or rapidly progressive morphea with systemic corticosteroids (eg, high-dose
intravenous methylprednisolone in monthly pulses or oral prednisone at various intervals) in combination with
weekly low-dose methotrexate (MTX) has been reported in several case series. MTX alone can also be effective
3-Phototherapy:
•UVA1(340-400), and psoralen produced marked clinical improvement because UVA1 wavelengths penetrate
deeper into the dermis. Unfortunately, the availability of UVA1 is currently limited
•Narrowband UVB therapy, although less potent owing to its limited dermal penetration, can also be beneficial
•Regimens combining UV therapy with topical corticosteroids or calcipotriene may be superior to either method
alone
2-GENERALIZED MORPHEA
•The etiology is similar to localized morphea
•The clinical picture shows plaques similar to those of loc. Morphea, but the plaques are commonly much larger
(many cm)
•The main areas involved are the upper trunk, breasts, abdomen, upper thighs&arms
•The legs,face, neck and scalp (with scarring alopecia) may also be involved
•Rarely,the whole of the body may be involved from the top of the head to the feet
•If the chest wall is markedly involved there may be difficulty in breathing
•In most cases, the skin slowly softens and the pigmentation decreases within 3-5 years
•Treatment:Similar to systemic and phototheray of localized morphea
3-SYSTEMIC SCLEROSIS
Etiology
•Incidence: Between 2.3 and 30 per million population
• Male:female ratio:1:3
•85% of patients present between the ages of 20 and 60 years
•The etiology of systemic sclerosis is unknown.
•The presence of vascular symptoms in virtually all patients suggests that vascular endothelial cell is either an
initial target or the primary dysfunctional cell in this disease
• The associated fibrosis in systemic sclerosis is caused by the increased production of collagen in the
subcutaneous tissue
•Scleroderma fibroblasts synthesize more collagen than those from normal controls
•Fibroblast function is modified by endothelial cell products. Raised levels of growth factors supports this
suggestion
•The presence of antinuclear antibodies in over 80% of patients suggests an autoimmune response. However, it is
not clear if this is a primary abnormality or results from cellular damage
•increased incidence of HLA-B8 in the more severe cases suggests that genetic factors play a part in the etiology,
but to date there appears to be no clear relationship between HLA,autoantibodies and clinical manifestations
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• Certain environmental factors may trigger occurrence of the disease:
•Vibration injury
•Silica
•Organic solvents (eg, toluene, benzene, xylene)
•Aliphatic hydrocarbons (eg, hexane used in shoes glues)
•Epoxy resin(used in adhesives as UHU)
•Pesticides
•Drugs (eg, bleomycin, cocaine, penicillamine, vitamin K)
•Appetite suppressants (eg, phenyl-ethylamine)
CLINICALLY
•The earliest feature is Raynaud’s phenomenon
•Less common early symptoms include gastro-oesophageal reflux and dysphagia
•Constipation, diarrhoea and abdominal pain are usually late features
Cutaneous changes:
•The hands and face are the most frequently involved
•The fingers may be swollen, and the skin feels tight and has a shiny appearance
•Hand ulcers may occur
•The facial appearance in a well-developed case is characteristic:
-The forehead is smooth and shiny, the skin is bound down and hard, the lines of expression are smoothed
out and the nose becomes small and pinched
-The mouth opening is constricted and radial furrows appear, giving a pursed appearance
-The lower eyelids cannot be depressed by the fingers to show the conjunctivae, because of atrophy of the
tissues
-Small mat-like telangiectases are frequently found on the face
Symptoms due to involvement of internal organs:
•GIT:
-Difficulty in swallowing solid foods can be followed by difficulty with swallowing liquids and subsequent
nausea, vomiting, weight loss, abdominal cramps,
blotting diarrhea, and fecal incontinence
Lungs:
-The patient can have shortness of breath on exertion and, subsequently, at rest
-The patient may have a nonproductive cough
-Atypical chest pain, fatigue, dyspnea, and hypertension may be present
•Musculoskeletal system:
-Joint pain, limitation of movement, joint swelling, and muscle pain may be present. Weakness is present in 80%
of patients
HISTOPATHOLOGY
•The dermis shows hyalinization of collagen,
•Cellular infiltrate consists of lymphocytes, plasma cells, fibroblastic type cells and macrophages, either
perivascular or diffuse
• In severely involved skin, the epidermis and its appendages are usually atrophic, with loss of the
INVESTIGATIONS
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rete ridges
•CBC:Anemia may be found in patients
with renal failure, gastrointestinal bleeding or malabsorption
•ESR is raised in about ½ of the patients
•Gammaglobulins level is elevated
•Antibodies against topoisomerase I DNA and Anticentromere antibodies may be detected in the serum
•The organs affected must be investigated e.g respiratory functions and x-rays on GIT
TREATMENT
•There is no specific treatment, and no therapy is known to alter the course of the disease
•Corticosteroids in low dosage may give a feeling of increased well-being and reduction of articular symptoms,
and in these cases maintenance on a low dosage of prednisolone, such as 5 mg once or twice daily, is justified
•Applications of 0.025–0.05% tretinoin may decrease perioral creases & facial tightening
•Vasodilators, e.g. nifedipine 10–20 mg 4 times daily may improve the blood flow in the fingers
•Antifibrotic agents have been investigated, although results have varied and none is clearly shown to be of
consistent benefit
•These have included D-penicillamine (Artamin) 500-1500 mg/day given over approximately 2 years may
decrease skin thickness, reduce the rate of further visceral involvement and improve the prognosis of patients if
given early in their disease particularly those with pulmonary involvement
•Immunomodulatory agents were also tried with variable results e.g.
-Photopheresis
-Methotrexate (15 mg/wk)
-Chlorambucil
-Cyclosporine
-Thalidomide
-Cyclophosphamide
-Statins
MIXED CONNECTIVE TISSUE DISEASE
•It is an overlap of three diseases, systemic lupus erythematosus, scleroderma, and dermatomyositis
•Some associations are more frequent than others; for example, systemic sclerosis combined with dermatomyositis
is more frequent than systemic sclerosis combined with SLE
•This overlap is associated with a specific antibody to U1-RNP, an ENA
•The patients are predominantly female
•They show features of SLE, systemic sclerosis, dermatomyositis and polymyositis
•Raynaud’s phenomenon, arthritis and arthralgia, sausage-shaped fingers and swelling of the dorsa of the hands,
abnormal esophageal motility, impaired pulmonary diffusing capacity and myositis
are frequent
•More than half the patients have the abnormal nail fold capillaries seen in systemic sclerosis
•Angiography shows obstruction of small blood vessels in almost 90% of cases
•Treatment: Corticosteroidsgives good results
•Other successful treatment options include hydroxychloroquine and methotrexate
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LICHEN SCLEROSIS ET ATROPHICUS
ETIOLOGY
•The male-to-female ratio is 1:6
•Up to 15% of cases are in children
•The cause of lichen sclerosus is unknown
•Autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been reported by several authors
•A history of preceding vaginitis or chronic balanitis, suggests that infection may play a provocative or localizing
part
CLINICALLY
Non-genital lesions
•The lesions on the skin are symptomless and occur on the trunk, and around the umbilicus, around the neck, in the
axillae, on the flexor surfaces of the wrists
•Lesions can occur at sites of pressure(koebner phenomenon) e.g.underneath bra straps or belts
•Lesions are small, ivory or porcelain-white, shiny, round macules or papules
•Typically their surface shows prominent dilated pilosebaceous or sweat duct orifices, which often contain yellow
or brown horny plugs
•In the later stages, atrophy occurs, andthe surface of the lesions becomes wrinkled, and may actually be
depressed
Anogenital lesions in women
•Lesions occur on the vulva and around the anus, and may extend to the skin of the inner side of the thighs
•There may be marked itching or the condition may be without any symptoms
•The ivory-colored atrophic papules with follicular hyperkeratosis and plugging can often be identified on the
vulva
•Gradual obliteration of the labia minora and stenosis of the introitus may occur
•Often, a figure-8 pattern involves the perivaginal and perianal areas
•More advanced cases may show eroded areas from which a biopsy should be taken to exclude coexistent
squamous cell carcinoma
Penile lichen sclerosus
In men, lichen sclerosus usually affects the tip of the penis, which becomes firm and white (balanitis xerotica
perstans)
•The urethra may narrow resulting in a thin stream
•The foreskin may become difficult to retract (phimosis)and a circumcision may be needed
HISTOPATHOLOGY
•There is hyperkeratosis, which often is thicker than the epidermis
•A lichenoid infiltrate in the dermal-epidermal junction
•Remarkable edema in the papillary dermis followed by a dense, homogenous fibrosis as the lesion matures
TREATMENT
For extragenital lesions
•There is no confirmed effective treatment
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•Calcipotriol may be helpful
•Phototherapy, including narrow-band UVB and low-dose UVA-1 has been reported to be of benefit
•Mycophenolate mofetil may be useful
For genital lesions:
•Potent topical steroid preparations gives both symptomatic relief and prevents scarring, and may induce complete
resolution of the problem
•Estrogen or testosterone containing creams have given symptomatic benefit, but testosterone are less effective
than topical steroids
•Etretinate and ciclosporin may be of benefit
•Carbon dioxide laser is also effective for genital lesions in both males and females
•Photodynamic therapy has been used to treat vulval disease
•Topical corticosteroids, sometimes for short periods under a condom, or intralesional injections of triamcinolone
may soften the sclerotic lesions of balanitis xerotica obliterans and reduce the phimosis
Scleroedema of Buschke
ETIOLOGY
•The etiology is unknown. Suggestions that have been considered include obstruction to lymphatic channels by
inflammation
•Sera from patients with paraproteinemia (presence of excessive amounts of a single monoclonal gammaglobulin
in the blood) stimulate collagen production in dermal fibroblast cultures
•Some persistent cases are associated with moderate to severe diabetes mellitus
•Although the condition may apparently start spontaneously, there is a history of an infectious episode, from a few
days to 6 weeks prior to onset, in 65–90% of cases
•It is usually influenza, tonsillitis, pharyngitis, measles, mumps, scarlet fever, impetigo or cellulitis; prior
streptococcal infections appear to be particularly common
•Sometimes, there is a history of trauma
•The condition is uncommon
•Occasional familial cases have been reported
•Females are more frequently affected than males in patients without diabetes, but scleroedema associated with
diabetes occurs predominantly in males
CLINICALLY
•Prodromal symptoms of slight fever, malaise, muscle and joint pains occasionally occur between the infectious
episode and the onset of induration
•Induration is usually symmetrical and often starts on the back and sides of the neck or on the face
•The face loses its expression, and the patient notices difficulty in wrinkling the forehead and in smiling. There
may be difficulty in opening the mouth
•The tongue and pharynx may be involved, with difficulty in swallowing
•Later, the shoulders, arms, hands and upper trunk become involved, but less frequently the abdomen and legs may
be affected
•The condition can be limited to the thighs
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•The induration is non-pitting and hard, and there is no sharp demarcation between normal and abnormal skin
Prognosis
•The condition may completely disappear in the course of some months to a few years, but a few may persist for
many years
HISTOPATHOLOGY
•The epidermis is normal
•The dermis may be three times its normal
•There is swelling and splitting of the dermal collagen bundles by an increase in ground substance
•Clear unstained spaces, or fenestrations, occur between the bundles in severe cases
•This process extends into the subcutaneous tissues, the fat of which is replaced by coarse collagen fibres
•The ground substance stains metachromatically with cresyl violet or toluidine blue. Metachromasia in
scleroedema is caused by the presence of hyaluronic acid [6], and is poorly seen in formalin fixed sections as the
hyaluronic acid is removed by the fixative
TREATMENT
•No effective remedy is known, although multiple therapies have been tried, including systemic and intralesional
corticosteroids
•Improvement with ciclosporin and electron beam therapy have been reported
•PUVA, UVA1, extracorporeal photophoresis and low-dose methotrexate are more recent suggestions
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