Autoimmune connective tissue disorders

A connective tissue disease is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules: collagen and elastin.

Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity). These are also referred to as systemic autoimmune diseases.

The autoimmune CTDs may have both genetic and environmental causes The autoimmune CTDs may have both genetic and environmental causes. Genetic factors may create a predisposition towards developing these autoimmune diseases. They are characterized as a group by the presence of spontaneous overactivity of the immune system that results in the production of extra antibodies into the circulation.

What Is Lupus? Lupus is a classic autoimmune disease whereby a misdirected immune system leads to inflammation and injury to one's own body tissues. Lupus erythematosus is a complex disorder associated with numerous clinical signs and symptoms and a wide range of laboratory abnormalities. It shows a spectrum of varying prognosis, ranging from a benign, solely cutaneous variant (localized discoid) through to a potentially fatal systemic illness

Lupus can involve the skin, joints, and internal organs Lupus can involve the skin, joints, and internal organs. The heart, lungs, and kidneys can also be affected in some patients. There is no specific cure, but treatments are effective at minimizing damage and improving function. Approximately 80% of lupus patients are women.

Lupus erythematosus: subtypes Discoid lupus erythematosus (localized) Discoid lupus erythematosus (generalized) Verrucous lupus erythematosus Subacute cutaneous lupus erythematosus Systemic lupus erythematosus Lupus erythematosus profundus Lupus erythematosus–erythema multiforme syndrome Drug-induced lupus erythematosus Chilblain lupus erythematosus C2 deficiency lupus erythematosus-like syndrome Neonatal lupus erythematosus

Lupus Erythematosus Chronic Cutaneous LE DLE Verrucous LE Lichen Planus-LE overlap. Chiblain LE Lupus Panniculitis (LE profundus) With DLE With Systemic LE

Discoid LE Young adults. F:M=2:1 Discoid lesions are characterized by discrete, erythematous, slightly infiltrated plaques covered by a well-formed adherent scale that extends into dilated hair follicles (follicular plugging). Lesions heal centrally first with atrophy, scarring, and dyspigmentation Up to 24% will have mucosal involvement. 95% of cases confine to the skin at the onset and will remain so.

Follicular plugging is evident in this patient with discoid lupus erythematosus involving the scalp.

Discoid lupus erythematosus: close-up view showing follicular plugging. By courtesy of the Institute ofDermatology, London,

Discoid LE Spontaneous involution with scarring is common Progression to SLE is rare and may be identified by abnormal labs. ANA – elevated Leukopenia, hematuria, or albuminuria

skin inflammation (dermatitis) hair loss can be temporary or permanent skin inflammation (dermatitis) hair loss can be temporary or permanent. Fortunately, permanent hair loss is less common than temporary hair thinning that recovers after a disease flare.

Discoid lupus of the scalp Discoid lupus affecting the scalp and face is shown. Note the discoid plaques over eyebrows, forehead, and scalp, with postinflammatory peripheral hyperpigmentation and central scarring, resulting in alopecia.

Histology Thinned epidermis Loss of normal rete ridges Follicular plugging Hydropic changes of basal layer Lymphocytic perivascular infiltrate Increase mucin DIF is positive more than 75% of case with Igs located at DEJ

Discoid lupus erythematosus: there is marked follicular plugging prominent periadnexal localization. Discoid lupus erythematosus: the follicular epithelium shows basal cell hydropic degeneration and there is a heavy lymphocytic infiltrate. Discoid lupus erythematosus: there is marked follicular plugging

Treatment SUNSCREEN!!!! Topical steroid, high potency with occlusion if needed Topical Tarcrolimos. Intralesional Injection with Kenalog Thalidomide Antimalarias: safest and most beneficial system therapy. Plaquenil for 3 month, if no response switch to Aralen. If response is still incomplete, change to Quinacrine

Verrucous LE AKA hypertrophic LE Resembling KA or hypertrophic LP Treatment as DLE

SCLE Subacute cutaneous LE Annular Papulosquamous Syndromes commonly exhibiting similar morphology Neonatal LE Complement deficiency syndromes

SCLE Psoriasiform, polycyclic annular lesions Shawl distribution: V neck, upper outer and inner arms. ¾ of the patients have arthralgia, 20% have leukopenia 80% have positive ANA Associated with Ro/SSA and HLA-DR3-Positive. Hydrochlorothiazide can induce SCLE

SCLE displays a superficial and deep perivascular infiltrate of lymphocytes with interface changes at the epidermis.

Systemic LE Young to middle age women Skin involvement occur 80% of the case American Rheumatism Association has 11 criteria If 4 or more of the criteria are satisfied, the patient is said to have SLE

ARA SLE criteria Malar Erythema Discoid Lupus Photosensitivity Oral Ulcers Arthritis Serositis Nephritis Hematologic CNS Changes Immunologic disorder ANA

Systemic Manifestation. Arthralgia is the earliest abnormality. 95% of SLE patient will have arthralgia. Avascular necrosis of femoral head. Thrombosis in vessels secondary to presence of lupus anticoagulant. Renal involvement in nephritic or nephrotic type. Myocarditis, cardiomegaly, EKG changes.

Systemic Manifestation. CNS involvement Ideopathic thrombocytopenic purpura. Sjorgen’s syndrom Mixed with dermatomyositis

An erythematous, edematous eruption is present on the malar area

Multiple gangrenous lesions of the toes due to necrotizing arteriolitis in a patient with systemic lupus erythematosus and severe Raynaud's phenomenon.

Treatment of SLE Treatment of depending on the organ system(s) involved. Skin, musculoskeletal, and serositis-type manifestations generally respond to treatment with hydroxychloroquine and nonsteroidal anti-inflammatory medications. Porphyria cutaneous tarda may co-exist with LE, in this case, Plaquenil is TOXIC!!! More serious organ involvement, such as CNS involvement or renal disease, often necessitates immunosuppression with high-dose steroids and cyclophosphamide.

Granular deposits of immunoglobulin G in the basement membrane zone on direct immunofluorescence of lesional skin.

LE-LP Overlap syndrome Large atrophic hypopigmented bluish-red patches and plaques. Response to treatment is poor Dapsone or Accutane maybe effective

Chilblain LE Chronic, unrelenting form of LE with fingertips, rims of ear, calves and heels in women. Chilblain lesions are due to cold Usual LE treatment

Lupus tumidus Round, erythematous plaques on the upper arm. the mucin stains with Alcian blue

LE Panniculitis AKA LE Profundus Deep subcutaneous nodules 1-4cm Head, face, and upper arms Woman age 20-45 Histology shows lymphocytic panniculitis, hyaline degeneration of the fat, hyaline papillary bodies. Over lying epidermis shows hydropic changes and follicular plugging Treatment with Antimalarials.

Biopsy of a patient with lupus profundus showing expansion of the interstices of the fat lobule with disintegrating leukocytes and fibrin.

Neonatal LE Annular scaling erythematous macules and plaques Appear on head and extremities First few months of life in babies born to mothers with LE, RA, or other connective tissue disease Resolve spontaneously by 6 month of age HALF of the patient has associated congenital heart block, usually 3rd degree

Predominant locations of inflammatory infiltrates in subsets of cutaneous lupus erythematosus . The types of cutaneous lupus erythematosus are: acute cutaneous lupus (ACLE), subacute cutaneous lupus (SCLE), chronic cutaneous lupus (CCLE), tumid lupus (TLE), and lupus panniculitis (LEP).The primary locations of the infiltrates are as follows: superficial dermis, ACLE and SCLE; superficial plus deep dermis and periadnexal, DLE; deep dermis, TLE; and subcutaneous fat, LEP.

Polymyositis/dermatomyositis Polymyositis is a rare inflammatory disorder of muscle, the etiology of which is unknown. If certain cutaneous lesions are also present, the term ‘dermatomyositis’is applied

Diagnostic criteria for polymyositis/dermatomyositis Symmetrical weakness of proximal limb muscles and anterior neck flexors plus esophageal and respiratory muscle involvement Positive muscle biopsy features Elevated skeletal muscle enzymes Appropriate electromyographic features A typical rash Either of these conditions may be confidently diagnosed if a patient fulfills the first four criteria (polymyositis) or three of the four plus the typical rash (dermatomyositis)

Variants of polymyositis Type Variant I Polymyositis II Dermatomyositis III Type I or II plus malignancy IV Childhood polymyositis or dermatomyositis V Overlap syndromes

Dermatomyositis Gottron's papules - flat-topped violaceous papules Heliotrope - reddish -purple flush around the eyes Over knuckle streak erythema Shawl pattern Calcinosis Cutis may occur in oer half of the children with DM Associated with Malignancy

Dermatomyositis Symmetrical muscle weakness assoc c malignant neoplasm when over 40 periungual telangiectasia Prednisone 60mg until severity decrease. Sunscreen, antimalarial Mechanics hand: hyperkeratosis, fissuring, scaling involvement in the palm of the hand.

Muscle involvement Symmetrical muscle weakness Unable to raise arms to comb their hair Cardiac involvement with cardiac failure in terminal phase Amyopathic dermatomyositis or dermatomyositis sine myositis: DM without muscle changes

Interface dermatitis in biopsy of dermatomyositis . there is atrophy with effacement of the ridge pattern, basal cell hydropic degeneration

basal cell hydropic degeneration

chronic inflammatory cell infiltrate Vacuolated, granular or fragmented

Scleroderma Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma). In the more severe form, it also affects internal organs These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen).

Localized Morphea Smooth, hard, somewhat depressed, yellowish white, or ivory-colored lesions. Common on the trunk Margins surrounded by light violaceous zone or by telangiectases. Slowly involute over a 3-5 year period.

Generalized Morphea Widespread hard indurated plaque. No systemic involvement Resolution less likely than the localized version.

Atrophoderma of Pasani and Pierini Reduction of thickness of derma connective tissue Upperback and lumbar sacral area Benign course, usually resolve after few months or few years. No effect treatment Variant of morphea.

Linear Scleroderma Linear lesions extend to length of arms or leg Begin first decade of life May also occur parasagitally down the forehead, known as en coup de sabre Parry-Romberg syndrome: progressive facial hemiatrophy, epilepsy, exophalmos, and alopecia, maybe a form of linear scleroderma.

Progressive Systemic Sclerosis is rapidly progressing and affects a large area of the skin and one or more internal organs

Prognosis Skin involvement after 1 year of diagnosis: Group I – sclerodactyly alone – 71% 10 year survival rate Group II - Skin stiffness above metacarpal-phalangeal joints but not involving trunk – 58% survival rate. Group III – truncal involvement – 21% survival.

LAB Finding Topoisomerase I (formerly Scl–70) is present in 20-30% of patients with diffuse disease (absent in limited disease) and has an increased association with pulmonary fibrosis Anticentromere antibodies are present in about 60-90% of patients with limited disease and 10-15% with diffuse disease.

Systemic sclerosis: note the flexion contractures Systemic sclerosis: note the flexion contractures. The skin is bound down and appears atrophic. There is periungual erythema Systemic sclerosis: early stage showing characteristic swollen, sausage-shaped fingers

Systemic sclerosis: the fingertips are tapered Systemic sclerosis: (microstomia)there is perioral scarring with atrophy

Systemic sclerosis: extensive telangiectasia as seen in this patient is more often a feature of the limited variant

Histology Increased collagen bundle and thickness of the derma. Pilosebaceous units are absent. Eccrine glands and ducts are compressed by collagen. Eccrine glands present at the mid dermis rather than at the junction of dermis/subQ fat.

There is a dense sclerosis of the dermis with decreased adnexal structures, and ‘trapping’ of remaining adnexal structures encased by collagen. Sparse perivascular lymphocytes are present.

CREST Syndrome AKA Thibierge-Weissenbach Syndrome. Systemic sclerosis may be limited to the hands, and is called acroslerosis. Not as severe as PSS ANA shows anticentromere antibody, and is highly specific. Most favorable diagnosis

Calcinosis (the deposition of calcium nodules in the skin), Raynaud's phenomenon (exaggerated vasoconstriction in the hands, with fingers undergoing white-blue-red color transitions in the cold), Esophageal dysfunction (leading to difficulty swallowing), Sclerodactyly (skin thickening on the fingers), and Telangiectasias (dilated capillaries on the face, hands and mucous membranes).

Treatment of morphea and lichen sclerosus Treatment of morphea and lichen sclerosus. +++ Highly effective; ++,effective +, moderately effective; 0, low efficacy or ineffective. 1, double-blind controlled trials; 2, clinical trial; 3, anecdotal report.

Eosinophilic Fasciitis Patient engaging in strenuous muscular effort few days or week before acute onset of weakness. Follow by severe induration of the skin and subQ tissue of forearms and legs. Coarse peau d’orange appearance. Groove sign: depression follow the course of underlying vessles when arms are hold laterally. Excellent response to corticosteroid.

Comparison of deep morphea and eosinophilic fasciitis Comparison of deep morphea and eosinophilic fasciitis. A Note the ‘pseudo-cellulite’ appearance of the involved skin of the thigh in deep morphea. B In eosinophilic fasciitis, the level of fibrosis is also deep.

Histology Patchy lymphocytic and plasma cell infilrate in the fascia and subfacial muscle and great thickening, 10-50 times normal of the fascia.

Mixed Connective Tissue Disease As originally defined by Sharp et al., mixed connective tissue disease (MCTD) represents a clinical condition in which patients have an overlap of signs and symptoms of systemic sclerosis, systemic lupus erythematosus, and polymyositis/dermatomyositis

Clinical features include: arthralgias and nondeforming arthritis, swollen hands with tapered or sausage-shaped fingers, Raynaud's phenomenon, abnormal esophageal motility,myositis, lymphadenopathy, fever, hepatomegaly, serositis, and splenomegaly In addition, their sera invariably contained high titers of antibody to a saline extractable nuclear antigen (ENA), U1-RNP, and speckled antinuclear antibody

Sjogren’s Syndrome AKA Sicca syndrome Triad of keratoconjunctivitis sicca, xerostomia, and rheumatoid arthritis. RF is usually positive Elevated C-reactive Protein, IgG, IgA, and IgM 80% has anti-Ro/SSA antibody. >50% have anti-La/SSB antobodies Only symptomatic treatment available.

The end

Rheumatoid Nodules 20-30% of RA patients Subcutaneous nodules Found anywhere on the body Histologically shows dense foci of fibrinoid necrosis surrounded by histiocytes in palisaded arrangement.

Relapsing Polychondritis Intermittent episodes of inflammation of the articular and nonarticular cartilage eventualing in chondrolysis. MAGIC syndrome = Behcet’s + Relapsing Polychondritis (Mouth And Genital ulcers with Inflamed Cartilage) Treatment with Dapsone for few weeks, then maintenance for 4-6 asymptomatic months.