Connective Tissue DiseasesSjogren’s Syndrome

Idiopathic Inflammatory Myopathies IIM, Scleroderma

• A 52-year old female grade-school teacher presents with a two-year history of extreme fatigue, and oral dryness. She has noticed increased difficulty getting through a full day at school due to muscle/joint pain, fatigue, and difficulty speaking. She is menopausal. You ask about dryness of the eyes and she admits to frequent use (4 times per day) of artificial tears and photosensitivity. She describes some type of rash when she goes into the sun.

• The oral exam is significant for mucosal dessication, fissured tongue, and dental decay. She exhibits muscle trigger point tenderness on the back of the neck, shoulder, elbows, knees, lower back and hips. She complains of joint pain in the knees and hands. No signs of vasculitis, skin rash, or joint swelling are observed.

Which of the following should be included in the differential

diagnosis? ?

• Fibromyalgia

• Primary Sjogren’s syndrome

• SLE

• Secondary SS with SLE

• Secondary SS with RA

• All of the above

Sjogrens syndrome• A chronic, systemic, autoimmune,

inflammatory disorder with lymphocytic infiltration , destruction of exocrine glands (lacrimal , salivary) and production of autoantibodies.

• Xerostomia -dry mouth

• Keratoconjunctivitis sicca- dry eyes

• Also affects: lungs(pneumonitis), kidneys ( instertitial nephritis), heart, skin (vasculitis), nervous system, hematopoietic system.

Epidemiology

• Incidence 4/ 100 000

• F / M – 9:1

• Onset 35- 50 years of age

• Genetic predisposition

• Family clustering

SS

• Primary SS– K.Sicca – aqueous tear deficiency– Xerostomia – hyposalivation

• Secondary SS– Primary SS + another Rheumatological

condition• RA, SLE, Ssc

Clinical course SS

• Slowly progressive

• Risk of developing Lymphoma 3-5% in life time in Primary SS

• Mortality ratio for PSS similar to normal population

Systemic involvement

• Cutaneous – dryness and pruritus

• Vasculitis – – palpable or non palpable purpura of the lower

extremities– In crops and may ulcerate– Urticarial vasculitis– Nodular vasculitis

Systemic involvement

• Upper airway ds– Recurrent non-allergic rhinitis / sinusitis– Dry cough– Bronchial dryness – mucus plugging

• Lung Disease– ILD – most common– Bibasilar crepitation, before cough/DOE

Systemic involvement

• Heart Ds

• Echocardiographic evidence of past pericarditis

• Hypokinesia LV

• Congenital heart block in infants and adults related to anti – SSA

Systemic involvement

• GI and Hepatic– Disphagia– Esophageal dysmotility– Nausea, epigastric pain, dyspepsia– Primary biliary cirrhosis

Systemic involvement

• Renal Disease– Instertitial nephritis

• Dysuria

• Urinary frequency

• Nocturia

• And urgency in the absence of infection

– Mild proteinuria

Systemic involvement

• Genitourinary – Dyspareunia – Interstitial cystitis

• Neuropathies – Peripheral – “glove and stocking”

• Fatigue

• Endocrine disorders – thyroid ds

Other clinical features

• Non – erosive arthritis/arthralgias

• Raynaud’s

• Lymphadenopathy

• Vasculitis

• Myositis

Criteria for the classification of Sjögren’s syndrome

• Ocular Symptoms• Oral Symptoms• Ocular Signs• Schirmer test < 5 mm• Rose Bengal score ³ 4• Histopathology ³ 1 agglomeration of 50 or more mononuclear cells/4mm• tissue (focus score)• Objective evidence of salivary gland involvement• Autoantibodies• SSA/Ro, SSB/La, ANA, RF • (4 or > high sensitivity and specificity)• Exclusions: lymphoma, sarcoid, GVH, acquired immune deficiency

Sjögren’s syndrome: evaluation

• Schirmer test – measures tear production via mm of wetness

• Rose Bengal or fluorescein stain – detects disruption or devitalized tissue

• Salivary flow – amount of saliva produced

• Dental evaluation

• Minor salivary gland (lip) biopsy – looking for lymphoid infiltration

• Serologic tests (SSA(Ro), SSB(La), ANA, RF)

• SPEP, cryoglobulins

• Lymph node biopsy

• Evaluation for renal tubular acidosis

SS – diff dx oral dryness

• Drugs • Tricyclics antidepressants

• Cold remedies

• Antihystamines

• Diuretics antihypertensives

• Anti – cholinergics

• Acute anxiety or depression

• Mouth breathing

• Autoimmune Ds

• Viral cond. HIV, Hep C

• Central brain lesions – Alzheimer’s, Multiple Sclerosis

• Head and Neck radiation

• Congenital absence of salivary glands

Questions-hyposalivation

• Do you have to drink water at night?

• Do you keep water at bedside?

• Can you swallow a cracker w/o water?

• Do you become easily choked?

• Recent increased dental decay?

• Change in the way food taste ?

• Yes response – support hyposalivation

DDx for SS

• SLE

• Sarcoidosis

• Fibromyalgia

• Fatigue and depression

• Other causes for parotid gland enlargement

Diagnostic procedures• H & P

• Lab studies– CBC, BUN, Creatinine, LFT’s, Hep C, HIV, RF,

ANA, anti Ro/SSA, anti La/SSB– Sm RNP– Immunoglobulins, UA

• Chest Xray

• Rose bengal, Schirmer test, Salivary flow rate by Tech 99 uptake, MRI

• Labial salivary gland biopsy

Treatment for SS

• First Goal symptomatic

• Minimize serious outcomes• Lung transplant

• Blindness

• Loss of teeth

• Depression and

• Disability

Pharmacological Management

• Ocular dryness

• OTC eye drops – Systane and Refersh tears

• Rx: Cyclosporine eye emulsion 0.05% (Restasis)

Pharmacological Management• Oral Dryness

– OTC: Sugar free chewing gum, and lozenges– Rx:

• Evoxac (Cevimeline) TID

• Salagen (Pilocaroine) 3-4 time per day

(Both muscarinic cholinergic agonists)

– Avoid in patients with angina, heart block, glaucoma, severe asthma

– Side effects: sweating, flushing , polyuria, visual blurring and decreased nigh vision

Oral health

• To treat Xerostomia, Candidiasis, dental and periodontal problems

• Oral hygiene, tooth brusing, , flossing, dental prophylaxis every 4 months, fluoride applications

• Artificial saliva

• Avoid drugs that worsen dry mouth

Oral Candidiasis Treatment

• Mycelex (Clotrimazole 10 mg lozenges)• suck on one 4-5 times per day

• Fluconazole 100mg– Two tables PO on day one , then one per day

for two weeks

Systemic therapies

• Plaquenil (Hydroxychloroquine)

• Arthralgias, skin manif. and fatigue

• Methotrexate

• Prednisone

• Rituximab

Sjögren’s syndrome: parotid gland

Sjögren’s syndrome: B-cell lymphoma, parotid gland

(clinical and photomicrograph )

Sjögren’s syndrome: cornea (Rose Bengal stain)

Sjögren’s syndrome: Schirmer test

Sjögren’s syndrome: xerostomia

Sjögren’s syndrome: parotid gland (photomicrograph)

Sjögren’s syndrome: parotid gland (sialograms)

• CASE # 2• 57 year old white female presents to the primary care clinic to establish care. She has noticed thickening of the skin on her hands that she initially attributed to an allergy to dishwashing detergent. However, she has become increasingly concerned since it has traveled up to her elbows bilaterally and started involving her feet and shins. She has difficulty making a fist due to the skin thickening.

• Additionally, she has been noticing weakness doing simple tasks like getting up off a chair. Physical exam reveals sclerodactyly extending up to the elbows on the upper extremity and up to the mid-shins on the lower extremity. There is evidence of muscle wasting over the biceps and quadriceps with 3/5 muscle strength of the hip flexors. Initial laboratory evaluation was unremarkable except for an elevated CPK of 10,000.

What is the diagnosis?

• Limited Scleroderma• Diffuse Scleroderma• Scleroderma/myopathy Overlap• Polymyositis

• The patient in this case presents with skin involvement suggestive of limited scleroderma. However, the proximal muscle weakness with elevated CPK is suggestive of muscle inflammation or myopathy. Muscle encasement due to sclerodermatous involvement of the fascia can cause elevated CPK and weakness as can a concomitant inflammation of the muscle itself. There is no data in the case to make the definitive diagnosis of polymyositis such as a muscle biopsy or antibodies therefore the answer is:

• C, scleroderma with some form of myopathy. While this disease conglomerate can be seen in conjunction with several other autoimmune diseases including SLE, nothing in this patient presentation seems to suggest a diagnosis of SLE. Classical skin manifestations of SLE are malar/discoid facial rash, alopecia and oral/nasal ulcers, which this patient does not have.

Subsets of Systemic Sclerosis

• Diffuse cutaneous syst.sclerosis

• Limited cutaneous syst.sclerosis

• Overlap syndromes• Diffuse or limited with features of other CTD

• Mixed connective tissue disease MCTD

• Localized sclerodrema• Morphea

• Linear scleroderma

Scleroderma

• Systemic sclerosis– With diffuse scleroderma: rapidly progressive skin

thickening (proximal to elbows and knees), early visceral disease (lung, heart and kidney)

– With limited scleroderma: restricted and non progressive skin thickening (distal extremities), delay visceral involvement (CREST)

– With overlap: diffuse or limited with features of other CTD (PM, DM, SLE)

SSc Pathogenesis

• Susceptible host

• Triggering event

• Activation immune system

• Endothelial cell activation

• Activation fibroblasts

• Obliterative vasculopathy and Fibrosis (increased collagen deposition)

SSc Epidemiology

• Incidence 15-20 cases per million

• Females predominant F:M – 5:1

• Age of onset 30-50 years of age

• More severe in African American

Scleroderma

• DCSS-– proximal and distal skin thickening involves

face / neck and trunk– Symmetric involvement fingers, hands, arms

and legs– Rapid onset after Raynauds– Auto-Ab present– Overall prognosis poor

Scleroderma

• LCSS:– CREST– Limited to symmetrical changes on

fingers(sclerodactyly), distal arms and face and neck

– Later visceral disease – Abs present – Good prognosis

Scleroderma Cutaneous Manifest.

• Skin thickening

• Telangectasias

• Digital pitting scars

• Calcium deposition

• Skin ulceration

Other clinical manifestations

• Musculoskeletal – Arthralgias and myalgias– Synovitis, tendonitis

• GI– Small oral aperture– Esophageal dysfunction– Bowel dysmotility

Cont.

• Pulmonary:– Fibrosis and inflammation with ILD

• Cardiac– Myocarditis, pulmonary HTN, arrhythmias

• Renal – Scleroderma renal crisis, renal failure

ACR systemic sclerosis: preliminary classification criteria • Major criterion or• two minor criteria for diagnosis

• Major criterion• Proximal scleroderma

• Minor criteria• Sclerodactyly• Digital pitting or scars or• loss of substance from finger pad• Bibasilar pulmonary fibrosis

Scleroderma-like syndromes

• Toxin- or drug-induced scleroderma– Organic solvents and epoxy resins– Eosinophilic myalgia syndrome (L-tryptophan)– Bleomycin

• Vibration injury

• Scleromyxedema

• Eosinophilic fasciitis

• Graft-versus-host disease

Raynaud’s phenomenon

• Episodic, reversible digital skin color change– white to blue to red– well-demarcated

• Due to vasospasm

• Usually cold-induced

• Primary (Raynaud’s disease) and secondary forms

Causes of secondary Raynaud’s phenomenon

• Connective tissue diseases– Scleroderma, systemic lupus erythematosus, MCTD, undifferentiated CTD,

Sjogren’s syndrome, dermatomyositis

• Occlusive arterial disease– Atherosclerosis, anti-phospholipid antibody syndrome, Buerger’s disease

• Vascular injury– Frostbite, vibratory trauma

• Drugs and toxins– Beta blockers, vinyl chloride, bleomycin, ergot, amphetamines, cocaine

• Hyperviscosity/cold-reacting proteins– Paraproteinemia, polycythemia, cryoglobulinemia, cryofibrinogenemia, cold

agglutinins

Raynaud’s phenomenon: hands

Scleroderma: Raynaud’s phenomenon, cyanosis of the

hands

Scleroderma: skin induration, hands

Scleroderma: acrosclerosis

Scleroderma: acrosclerosis and terminal digit resorption

CREST syndrome: calcinosis cutis, fingers

Scleroderma: calcinosis, hands

Scleroderma: leg ulcer

Scleroderma: facial changes, lateral view

Scleroderma: Mauskopf, facial changes

Scleroderma: Mauskopf, facial changes

Linear scleroderma: en coup de sabre, scalp and forehead

Linear scleroderma: thigh and leg

Morphea: leg

Scleroderma: Raynaud’s phenomenon, hand (arteriogram)

Raynaud’s phenomenon: hand (angiogram)

Scleroderma: acrolysis (radiographs)

Scleroderma: calcinosis and acrolysis (radiograph)

CREST syndrome: arm (radiograph)

Scleroderma: pulmonary fibrosis (radiograph)

Scleroderma: wide-mouthed diverticula, colon (radiograph)

Scleroderma: kidney (arteriograms)

Scleroderma

• Rare connective tissue disease that has– Fibrosis– Vascular instability (intimal proliferation and

Raynaud’s)– Autoimmunity

Is it autoimmune?

• In some patients with scleroderma the ANA is positive

• Greater than 80% in limited scleroderma and 50% in diffuse scleroderma

CREST

• Old fashioned term but still used– Calcinosis– Raynaud’s– Esophageal dysmotility– Sclerodactyly– Telangiectasia

Limited vs Diffuse Scleroderma

Limited• Most positive ANA• 80% anticentromere• Rare renal, heart, lung

involvement• May develop PAH in

long standing disease

Diffuse• 50% ANA positive

usually nucleolar• Scl 70 in 30%,

correlates with pulmonary fibrosis

• Renal crisis with RNA polymerase

• Higher mortality

Sclerodactyly and pigmentation

Raynaud’s

• Primary– Not associated with any other disease

Secondary

Associated with connective tissue diseases such as SLE, scleroderma, RA, Sjogren’s, Polymyositis

Reversible color change of the digitals with pallor and then rubor and or cyanosis

Treatment: Raynaud’s

• Calcium channel blockers

• Cold avoidance

• Smoking cessation

• Other drugs

Proof of Treatment in Raynaud’s associated with Scleroderma

• Calcium channel blockers, esp Nifedipine– Small trials, can’t prove effectiveness for

healing of digital ulcers

Meta-analysis Arthritis Rheum 2001 44:1841-7

Prostacyclins/ Prostaglandin analogues

• Iloprost• Very effective in IV(5 trials), less effective po (1

trial) • Effective in RP frequency and severity of attacks

and at healing and preventing digital ulcers• Beraprost - effective for recurrent digital ulcers

J Rheumatol 1999, 26:2173-8

Treatment: GI Tract• Proton pump inhibitors are very effective

for GERD• Anti-reflux maneuvers include: not eating

after supper, raising the head of the bed, pro-kinetic drugs to propel food through the stomach

• Small bowel overgrowth can be treated by antibiotics on an intermittent basis

• Some drugs can help the bowels contract

Incontinence can also occur secondary to:

• Hypotonic bowel

• Poor anal sphincter tone

Diverticulosis can also occur in the bowel

Renal Involvement

• Renal crisis is a condition with high blood pressure (usually), hemolysis (intra-vascular), and worsening renal function

• Renal crisis is secondary to poor blood flow to the kidney, as well as kidney changes with scarring around the blood vessels

Renal Involvement (cont’d)

• Treatment has improved the mortality from scleroderma renal crisis, particularly rapid control of the blood pressure using ACE inhibitors

• Some patients do go on to temporary or permanent dialysis

Lung Involvement

Two main types:

• Interstitial lung disease (inflammation and scarring of the lung parenchyma)

• Pulmonary hypertension with high pressures in the arteries perfusing the lungs

• Pulmonary Hypertension (PAH) in scleroderma is either– Primary (vascular defect)– Secondary (Secondary to pulmonary fibrosis)– Or both

Prevalence in Scleroderma Related PAH

Treatment of PAH• Same as that for Primary Pulmonary HTN

(PPH)Vasodilators such as calcium channel blockersEndothelin receptor antagonist (Bosentan)Prostacyclin analogs: Epoprostenol (Flolan), IloprostAnticoagulationTreatment of CHF and dysrythmiaOxygenNitric Oxide

Bosentan

• Bosentan (Tracleer) is an Endothelin-1 antagonist

– Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen

Heart Involvement

• Patients with scleroderma can develop a cardiomyopathy with thickening heart muscles and reduced blood flow to the heart

• This is manifest by shortness of breath, angina or congestive heart failure

• It is treated the same way as congestive heart failure from other causes

Pleural and Pericardial Effusions

• These can occur in scleroderma, particularly in those with diffuse scleroderma

• Sometimes treated with prednisone

Arthritis in Scleroderma

• Many patients with scleroderma have arthralgia

• Some have inflammatory arthritis with swollen joints

• 20% on x-ray can have joint destruction• This is treated with anti-inflammatories,

physiotherapy, and sometimes disease-modifying drugs

Calcinosis

• Calcium deposits are under the skin in pressure areas

• They can break open and ooze white, chalky material

• They are often painful

Digital Tuft Resorption

• Patients with scleroderma can lose mass at their fingertips making them painful and appearing tapered or shortened

Digital Ulcers

• Digital ulcers occur in many patients with scleroderma

• They are painful• May take a long time to heal sometimes resulting

in gangrene or rarely necessitating amputation• Treatment with analgesics, blood thinners, and

new drugs (ie. Bosentan) are being studied for increased healing and a decrease in new ulcers

Digital Ulcers

other treatments are underway, including:

• Biologic drugs, such as antibodies to decrease TGF-beta (tumor growth factor beta), which is important in causing fibrosis in scleroderma

• Other biologic trials are being considered for patients, such as blocking cTGF, this is important in fibrosis and fibroblast production in scleroderma, and is also an important target

Targeted Therapies

• Anti TGFbeta antibodies – under development, 1st trial negative

• cTGF antibodies

• Targeting pathological pathways

• Stem cell transplant study

Scleroderma Mortality

• Similar to breast cancer (50% 5 year survival)• From:

– Interstitial lung disease

– Cardiomyopathy

– Pulmonary Hypertension

– “We have found that those with renal involvement still have a very high mortality and was the highest association of mortality in our cohort”

Conclusions

• Scleroderma is a rare connective tissue disease• It is accompanied by a lot of morbidity and at

times mortality• There are good treatments for symptom control of

various organ systems• There are some good treatments for reversing the

progression of the organ-specific disease, such as scleroderma renal crisis

• The future appears promising for direct targets that may help in the treatment of scleroderma

Idiopathic Inflammatory Myopathies

IIM

Idiopathic Inflammatory

Myopathies (IIM) • Adult polymyositis (PM)• Adult Dermatomyositis (DM)• Juvenile myositis (JDMS)• Malignancy-associated myositis• Myositis overlap with another rheumatic disease

• Inclusion body myositis (IBM)

IIM

• heterogeneous group of autoimmune disorders characterized by muscle weakness, inflammation and possible systemic complications.

IIM Epidemiology

• Rare disease

• Incidence 5-10 cases/ million

• Prevalence 50-90 cases /million

• F:M 2-3: 1

• African American women more affected

IMM Clinical• Proximal and symmetric muscle weakness

• Functional deficit from weakness• Difficulty raising their arms, combing the hair, getting up

from the chair, walking up steps, frequent falls

• Fatigue, joint pain , anorexia

• Elevated muscle enzymes:• CK, AST, ALT, aldolase, and LDH

• EMG abnormal

• Abnormal muscle biopsy

Proposed diagnostic criteria for

polymyositis and dermatomyositis • PM diagnosed as definite with 4 out of 5 of the below criteria or

probable with 3 out of 5• DM diagnosed as definite with rash plus 3 out of 4 of the below

criteria or probable with rash plus 2 out of 4 criteria– Symmetric proximal muscle weakness

– Elevated muscle enzymes (CPK, aldolase, transaminases, LDH)

– Myopathic EMG abnormalities

– Typical changes on muscle biopsy

– Typical rash of dermatomyositis

Polymyositis: differential diagnosis

• Polymyositis and dermatomyositis

• Hypothyroidism

• Drug-induced myopathies• Corticosteroids, colchicine, HMG-CoA reductase inhibitors, zidovudine,

hydroxychloroquine, alcohol

• Infections– Viral, toxoplasmosis, trichinosis, bacterial pyomyositis

• Connective tissue disorders– Lupus, scleroderma, MCTD

• Systemic vasculitis– PAN, Wegener’s granulomatosis

Polymyositis: differential diagnosis, cont’d

• Metabolic myopathies– Disorders of carbohydrate and lipid metabolism

• Electrolyte disturbances– Hypernatremia, hyponatremia, hypokalemia, hypophosphatemia,– hypocalcemia

• Inclusion body myositis

• Sarcoid myopathy

• Amyloid myopathy

• Neurologic disorders– Myasthenia gravis, motor neuron disease, muscular dystrophy

•

Inclusion body myositis

• Males affected more than females

• Age of onset usually greater than 50

• Slowly progressive

• Distal and asymmetric muscle weakness

• Myopathic and neuropathic changes on EMG

• Mononuclear cell infiltrates and vacuoles containing amyloid on• muscle biopsy

• Responds poorly to corticosteroids

Myositis-specific antibodies

ANTIBODY DISEASE ASSOCIATION PREVALENCE

Anti-tRNA synthetases (Jo-1)

Dermatomyositis, interstitial lung disease, “mechanic’s hands”

20%

Anti-SRP (signal recognition protein)

African-American women, poor prognosis

Rare

Anti-Mi-2 Older women, “shawl sign,” good prognosis

5%

PM/SCL Polymyositis/scleroderma overlap

Rare

Dermatomyositis: heliotrope rash

Dermatomyositis: diffuse facial erythema

Dermatomyositis: rash, chest

Dermayomyositis: macular rash and acanthosis nigricans

Dermatomyositis: “mechanic’s hands”

Dermatomyosistis: periungual involvement

Dermatomyositis: nailbed

Dermatomyositis and scleroderma: periungual involvement (nailfold

capillaroscopy)

Dermatomyositis: rash, knees

Dermatomyositis: subcutaneous calcification, knees

Steroid myopathy: muscle (photomicrographs)

Inflammatory myopathy (photomicrograph)

Polymyositis: heart (photomicrograph)

Dermatomyositis: calcinosis, thigh (radiograph)

IIM

• Dermatomyositis• Peaks in kids and

older adults• In elderly may be

perineoplastic – adenoca usually

• Rash, photosensitivity

• Polymyositis• Any age• No rash or

photosensitivity• Not perineoplastic

usually• Worse if interstitial

lung disease (anti Jo1)

IIM

• Rare• Diagnosis made by esp proximal muscle

weakness, elevated CK• Muscle biopsy shows degeneration and

regeneration of m bundles or with dermatomyositis perivascular inflammation

• EMG – spontaneous fibrillation potentials, abnormal action potentials

Other features

• Heliotrope rash

• Gottren’s sign/papules

• Photosensitivity

• Mechanics hand

• Livedo reticularis

• Some are overlaps with other connective tissues diseases

Antibody and Lab profile

• Increased CK (or aldolase), normal CBC• Occ increased ESR• May have + ANA, ENA such as PM/Scl or Jo1• Jo1 correlates with interstial lung disease and has

a bad prognosis and is very specifici• PM/Scl- often with scleroderma polymyositis

overlap

Treatment

• High doses of steroids

• Steroid sparing drugs such as Imuran, Methotrexate, Cytoxan

• Treatment and prevention of complications such as steroid induced osteoporosis

• Biologics possibly (TNF inhibitors)

• Lung disease needs aggressive treatment

Complications

• Esophageal involvement – aspiration

• Cardiac involvment – arrhythmia

• Cancer associated – death

• Heterotopic muscular calcification

• Raynauds – ulcers

• Sclerodactyly – flexion contractures