Connective Tissue Diseases Adam Wray, D.O. September 7, 2004 ANA Assay  Classic ANA immunofluorescence is still considered first      line screening test for AI-CTD Historically, rodent cells rather than human cells were used as the substrate Rodent cell nuclei lack some autoantigens present in human cell nuclei (Ro antigen) 1-2% of SLE patients are ANA (-) using human tumor cell line base substrate (Hep-2) Hence, “ANA negative SLE” a historical phenomenon Titer of <1:160 using human tumor cell line substrate has little clinical utility ANA Immunofluorescence Patterns Drug Induced ANA/SLE  Procainamide  Hydralazine  Isoniazid  Chlorpromazine  Phenytoin  Methyldopa  Minocycline 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  Cat’s Tongue (Langue au chat) = carpet tacks  Lesions heal centrally first with atrophy, scarring, and dyspigmentation  Up to 24% will have mucosal involvement.  95% of cases confined to the skin at the onset and will remain so. Discoid LE  Unusual for lesions below neck without lesions above the neck  Spontaneous involution with scarring is common  Progression to SLE is rare and may be identified by abnormal labs. – ANA – elevated – Leukopenia, hematuria, or albuminuria Histology         Thinned epidermis Loss of normal rete ridges Follicular plugging Hydropic changes of basal layer Lymphocytic perivascular infiltrate Increase interstitial mucin depositon Pilosebaceous atrophy discriminates from SCLE DIF is positive more than 75% of cases with Igs located at DEJ Treatment  SUNSCREEN!!!!  Topical steroid, high potency with occlusion if needed.  Intralesional Injection with Kenalog  Antimalarials: safest and most beneficial system therapy. – Plaquenil for 3 months, if no response switch to Aralen. – If response is still incomplete, add Quinacrine, since this won’t increase retinal toxicity Verrucous LE  AKA hypertrophic LE  Resembling KA or hypertrophic LP  Treatment with TAC or Intralesional  Also can be treated with Accutane or Plaquenil. Verrucous LE  2% of patients with chronic cutaneous LE  Histo: epidermis is papillomatous, hyperplastic, and surmounted by hyperkeratotic scale LE-LP Overlap syndrome  Large atrophic hypopigmented bluish-red patches and plaques.  Fine telangiectasia and scale usually present  Response to treatment is poor  Dapsone or Accutane maybe effective Chilblain LE  AKA lupus pernio  Chronic, unrelenting form of LE with fingertips, rims of ear, calves and heels in women.  Chilblain lesions are due to cold  Usual LE treatment 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. SCLE  Subacute cutaneous LE – Papulosquamous – Annular – Syndromes commonly exhibiting similar morphology • Neonatal LE • Complement deficiency syndromes SCLE  Typically photosensitive  Lesions confined to sun-exposed skin  Regular association with anti-Ro antibody (SS-A) 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 HLA-DR3-Positive. Drugs triggering anti-Ro antibodies and thus lesions of SCLE  HCTZ  NSAIDS  Diltiazem  Griseofulvin  Terbinafine  Lesions may or may not clear once the medication is discontinued. 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 patients have associated congenital heart block, usually 3rd degree Neonatal LE  Lesions histologically identical to SCLE  Almost 100% have anti-Ro antibodies  Unlike adult SCLE, lesions have predilection for the face, especially periorbital region  Lesions typically resolve without scarring  Other internal findings – Hepatobiliary disease – Thrombocytopenia Acute Cutaneous LE  Characteristic butterfly facial erythema  May last from days to several weeks  Bullous lesion occur as single or grouped vesicle or bullae  Subepidermal bulla containing neutrophils.  HLA-DR2 positive  Minute telangiectasias appear in time on the face or elsewhere and commonly appear about the nail folds.  Rowell Syndrome: EM-like lesion dominant in LE 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 secondaary to presence of lupus anticoagulant.  Renal involvement in nephritic or nephrotic type.  Mycocarditis, cardiomegly, EKG changes. Systemic Manifestation.  CNS involvement  Idiopathic thrombocytopenic purpura.  Sjogren’s syndrome  Mixed with dermatomyositis Treatment of SLE  Treatment 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.  Stop smoking! Dermatomyositis        Poikiloderma Gratton's sign - flat-topped violaceous papules Heliotrope - reddish -purple flush around the eyes Over knuckle streak erythema Shawl pattern Bimodal distribution Calcinosis Cutis may occur in over half of the children with DM  Associated with Malignancy in 10-50% of adults Dermatomyositis  Symmetrical muscle weakness  assoc c malignant neoplasm when over 40  periungual telangiectasia  Prednisone 1mg/kg with slow taper  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 Childhood DM  Brunsting type – Slow course – Progressive weakness – Calcinosis – Steroid responsiveness  Banker type – Vasculitis of muscles and GI tract – Rapid onset – Severe weakness – Steroid unresponsiveness Scleroderma  characterized by symmetric thickening, tightening, and induration of the skin of the fingers and the skin  These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen).  Occurs in localized and systemic forms Localized Morphea  Smooth, hard, somewhat depressed, yellowish white, or ivory-colored lesions.  Common on the trunk  Margins surrounded by light violaceous zone or by telangiectasias.  Resemble pigskin (prominent follicular orifices)  Slowly involute over a 3-5 year period. Generalized Morphea  Widespread hard indurated plaques.  No systemic involvement  Patient appear young because of the firmness of the skin.  Resolution less likely than the localized version. Atrophoderma of Pasani and Pierini  Reduction of thickness of dermal 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. 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 Progressive Systemic Sclerosis  Raynaud’s is the first manifestation of PSS most of the time and is eventually nearly always present  Round fingerpad sign: loose the normal peaked contour and appear round from the side.  Pterygium inversum unguis: distal part of nailbed remains adherent to ventral surface of nail plate. Seen also in LE Progressive Systemic Sclerosis  75% have dilated nail fold capillary loops  Esophageal involvement in 90% of patients  Pulmonary fibrosis  Cardiac involvement  Articular pain, swelling, polyarthritis. Prognosis  Skin involvement after 1 year of diagnosis:  Group I – sclerodactyly alone – 71% 10 year survival rate  Group II - Skin stiffness above metacarpalphalangeal 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. Histology  Increased collagen bundle and thickness of the dermis  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. Treatment  Symptomatic tx  Treatment aimed at minimizing complications  Regular massage, warmth, and protection from trauma  No smoking 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 follows the course of underlying vessels when arms are held laterally. Represents line of demarcation between muscle groups  Excellent response to corticosteroid. 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  Mixed features of scleroderma, SLE, and dermatomyositis  IgG deposition in speckled (particulate) pattern in epidermal nuclei of normal skin on DIF is a distinctive finding in MCTD  Treatment with daily dose of prednisone 1mg/kg shows good improvement.  Most patients have anti-U1RNP antibodies 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.  Labial salivary gland biopsy most definitive test Schirmer test  Assesses lacrimal gland function  Whatman paper wick folded over eyelid for 5 minutes  <5mm tear film migration = lacrimal gland dysfunction 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 eventuating 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.