Connective Tissue Diseases Adam Wray, D.O. September 7, 2004

Example of autoantibodies with considerable disease specificity and good for diagnosis are boxed. Anti-ds DNA and Sm for SLE Mi-2 for classic dermatomyositis Jo-1 for anti-synthetase syndrome Scl-70 (aka topoisomerase) and centromere for different forms of systemic sclerosis However, most autoantibodies fall into the disease nonspecific category, as illustrated. As shown, high levels of U1RNP with overlapping features of all four of these AI-CTD defines the concept of MCTD

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 Reference: Bolognia, Ch. 42, p. 592

ANA Immunofluorescence Patterns Detection of antinuclear antibodies on Hep-2 tumor cells. A–D Homogenous pattern; speckled pattern; nucleolar pattern; Anti-centromere antibodies. E Anti-double-stranded DNA antibodies binding to the flagellate Crithidia luciliae by indirect immunofluorescence. These patterns have little disease specificity with exception of centromeric (discrete speckled) = CREST Peripheral (rim) suggests antibodies to ds-DNA SLE Nucleolar suggests SSc Speckled (particulate) suggests presence of antibodies to U1RNP  MCTD

Drug Induced ANA/SLE Procainamide Hydralazine Isoniazid Chlorpromazine Phenytoin Methyldopa Minocycline Minocycline recently added to the list. Reference Bolognia: Ch. 42, p. 592

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.

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.

Chronic cutaneous lupus erythematosus (CCLE) with discoid lesions Chronic cutaneous lupus erythematosus (CCLE) with discoid lesions. The ear is a common site of involvement. Note the central depigmentation and scarring. In addition to the obvious, intensely inflamed, indurated lesion on the side of the face, there is a small lesion in the uppermost portion of the concha of the ear.

The widespread discoid lesions in this person resulted in depigmentation on the face, arms, and trunk.

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

prominent periadnexal localization of inflammation similar to SCLE

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

Lupus pernio. Violaceous plaques on toes, some with scale.

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.

Lupus panniculitis. The deeply indented lesions of the arms represent lupus panniculitis. The patient also had lesions on the face, upper trunk, breasts, and thighs.

There is a lobular panniculitis with a dense infiltrate of lymphocytes, plasma cells, and macrophages. Focal hyalinization of the adipocytes is present.

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) Subacute cutaneous LE (papulosquamous pattern).

Effect of ultraviolet (UV) radiation on tissue response Effect of ultraviolet (UV) radiation on tissue response. UV light causes Ro antigen to move to the cell surface, where they bind to anti-Ro antibodies. Women with anti-Ro antibodies may be asymptomatic or have sicca symptoms, photosensitivity, and/or arthralgias. These women are at increased risk for having babies with 3rd degree heartblock, SCLE, hepatobiliary disease, thrombocytopenia, or some combination of these.

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. Subacute cutaneous LE (annular-polycyclic pattern). The annular plaques have an erythematous scaly border, the central area is hypopigmented, and the eruption is confined to the back and hands.

Subacute cutaneous lupus (SCLE) lesions Subacute cutaneous lupus (SCLE) lesions. There are non-scarring, erythematous, slightly scaly plaques on the upper trunk and arms. Annular plaques with crusted margins.

The lesions on the hands conform to the typical distribution of lupus lesions, sparing the knuckles.

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

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

Neonatal lupus. Annular erythematous plaques with a slight scale usually appear on the head slightly after birth. Sun exposed areas of the arms and trunk may also be involved. Telangiectasia is often prominent. Skin lesions resolve with time.

Erythematous, atrophic, annular plaques distributed on forehead, periorbital ridge, and temples, with no associated scale or telangiectasia.

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

Butterfly rash

Acute cutaneous lupus (ACLE) Acute cutaneous lupus (ACLE). The patient shown in this photo had ACLE lesions on the arms as well as the face.

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

Other cutaneous manifestations include subungual telangiectasias, erythema and edema of the digits and diffuse nonscarring alopecia

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! Benefits of discontinuing smoking related to the fact that smoking may make antimalarial therapy less effective.

Laboratory approach to diagnosis

Histologic approach

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 Poikiloderma most important diagnostic feature of the cutaneous eruption of dermatomyositis. Poikiloderma violaceous in dermatomyositis and red in SLE

Poikiloderma in dermatomyositis.

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 Banker type Slow course Progressive weakness Calcinosis Steroid responsiveness Banker type Vasculitis of muscles and GI tract Rapid onset Severe weakness Steroid unresponsiveness

Violaceous poikiloderma of the face

Violaceous poikiloderma of the face, plus thin plaques on the elbows that are sometimes misdiagnosed as psoriasis.

Gottron's sign with violaceous poikiloderma over the knuckles.

Calcinosis cutis on the abdomen of a child with dermatomyositis

Interface dermatitis in biopsy of dermatomyositis .

High power view of vacuolar alteration of basal layer

Diagnostic criteria includes: symmetrical weakness of proximal and limb girdle muscles, elevated muscle enzymes (CK, aldolase, LDH, transaminases), abnormal EMG, and triceps muscle bx with associated cutaneous findings. If findings equivocal, then consider MRI or ultrasound

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.

Early inflammatory plaque type morphea of the trunk

Plaque-type morphea of the trunk.

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.

Atrophoderma of Pasini and Pierini Atrophoderma of Pasini and Pierini. A Multiple depressed, slightly hyperpigmented patches on the back. B Coalescent hyperpigmented patches on the abdomen.

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.

Linear morphea of the leg

Morphea en coup de sabre

Parry–Romberg syndrome

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

Matted telangiectasias

Calcinosis cutis of the thumb in a patient with scleroderma

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 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.

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

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.

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 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 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.

In the septae of the subcutis and fascia there is fibrosis and numerous inflammatory cells, including lymphocytes, histiocytes, and plasma cells. No eosinophils were found.Comments:A complete blood count demonstrating an eosinophilia and tissue eosinophilia on skin and fascial biopsy are not a prerequisite for the diagnosis of eosinophilic fasciitis. These histologic findings are consistent with the diagnosis.

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.

Erythema and swelling of the ear with sparing of the earlobe (no cartilage)