connective tissue diseases

Connective Tissue Diseases

Betsy Evans PA-CRheumatology Associates

Portland, ME

Systemic Lupus Erythematosis(SLE)

• Multi- system variable autoimmune disease of unknown etiology

• Rare: 40-150 cases/100,000• Hormones play a role!– Adult female:male 7-15:1• Children female:male 3:1

– Age of onset: 65% between 16-55 yrs– Later onset (>50) usually has milder disease

Pathophysiology

• Precise mechanism is still not known but abnormal cell apoptosis resulting in cellular breakdown and cellular antigens appear to play key role in the formation of polyclonal B-cell activation and autoantibody production. These lead to immune complex formation and deposition, resulting in complement-dependent inflammation of involved organs

Race Plays a Role

• SLE occurs 3x more common in Afro-Americans than whites

• Disease is more prevalent and tends to be more severe in Asians, Afro-Americans, Afro-Caribeans & Hispanics

• More common in urban areas

Clinical Features• Must meet 4/11 Criteria defined by the American

College of Rheumatology:– Malar rash– Discoid rash– Photosensitivity– Oral or nasal ulcerations– Arthritis of 2 or more joints– Serositis (pleuritis or pericarditis)– Renal disorder– Neurologic disorder– Hematologic disorder– Immunologic disorder– Antinuclear antibody

Other Nonspecific Sxs of SLE

• Raynaud’s Phenomenon: fingers turn stark white, followed by blue and then painful red when they re-prefuse upon cold/stress exposure

• Unexplained Fever• Alopecia• Fatigue• Myalgias/arthalgias

Malar Rash

Discoid Rash

Oral Ulcerations

Arthritis

Renal Involvement

• Nephritis (5 different classes)• Nephrotic Syndrome• Tubulointerstitial disease

• Clinically look for persistant proteinuria and cellular casts

• Definitive diagnosis by biopsy

IgG Deposition, Glomerulus

Membranous Lupus Nephritis showing immune complex deposition

Neurologic Involvement

• Seizures

• Psychosis

Hematologic Involvement

• Hemolytic Anemia• Leukopenia• Lymphopenia• Thrombocytopenia

Immunologic Disorder

• Antiphospholipid Syndrome– A syndrome characterized by vascular thrombosis

(can be arterial or venual), pregnancy mortality, + anticardiolipin Abs

• +Lupus anticoagulant• Antibodies to double-stranded DNA• False positive serologic test for syphilis

ANA Patterns

• Various patterns react to different parts of a cell• ‘Diffuse’ or ‘homogenous’ pattern is the least

specific but can be associated with SLE if titers are high (usually >1:512)

• dsDNA is the most specific; speckled and nucleolar are also important

• Histone pattern -> think DRUG INDUCED!• Centromere pattern -> think CREST Syndrome

Drug Induced Lupus

• Can act and look like SLE but entirely reversible once the offending drug is d’ced.

• Known Offenders: Hydralazine, Procainimide, Minocycline, Chlorpromazine, Isoniazid, Penicillamine, Methyldopa, & Interferon-alpha

Discoid Lupus

• Subset of lupus limited to the skin• Diagnosis confirmed by skin biopsy• ANA often negative• Prognosis usually good; <10% develop SLE

SLE Clinical Course

• Highly variable. 5 year survival rate >90%• Poor prognostic indicators:– Renal disease– CNS disease– Early or late age– Males– Non whites– Overall disease activity

Clinical Course cont’d

• Late in disease (>5 years) complications/death more likely due to thromboembolic disease– ? Due to steroid requirements vs chronic

inflammatory states

SLE Diagnostic Studies

• Good History and ROS!• Tissue biopsy if suspect renal involvement• Labs: CBC (look for cytopenias, anemia)– BUN/Cr (renal disease)– UA (proteinuria/cellular casts)– ANA (increased- watch the pattern)– C3/C4 (decreased)– CRP (normal or increased)– ESR (increased)– Ds DNA (present)

SLE Interventions/Therapeutics

• Depends on the severity of disease• Hydroxychloroquine helpful for fatigue and skin

rashes• Renal disease often requires high dose

corticosteroids and/or powerful immunosuppressants like Cyclophosphamide

• Other immunosuppressants often used and considered ‘steroid-sparing’: Azathioprine, Mycophenalate, Methotrexate

SLE Interventions

• Other considerations:– Treat side effects of medications eg

atherosclerosis and osteoporosis– Pregnancy can be very risky for a female with SLE.

Effective birth control and family planning are important. All efforts to have her disease under excellent control prior to conception and then close monitoring during pregnancy for any flares are imperative

SLE Final Thoughts

Don’t rely on the ANA to make or break the diagnosis; instead listen to your patient and look for other criteria. If they aren’t present, it probably isn’t SLE.

If in doubt, refer to a Rheumatologist for evalDon’t be fooled by a low titer + ANA- remember

it is NONSPECIFIC!

SCLERODERMA

Systemic Sclerosis (SS)CREST Syndrome

Scleroderma

• From the Greek “scleros”, describing thickened, hardened skin

• 2 forms: Systemic Sclerosis (SS) and Crest Syndrome (limited)

• Very rare: 240 cases/million• Cause unknown• Females>>males, peak onset 30-50 y.o.

Scleroderma Pathophysiology

• Poorly understood. Unknown trigger in a genetically susceptible person leads to immune system activation and vascular reactivity followed by the deposition of collagen and other matrix proteins in affected tissues.

Clinical Presentation of SS• Skin: Raynaud’s phenomenon with diffuse thickening including

chest, abdomen, face, upper arms, shoulders as well as hands and feet

• Pulmonary: interstitial lung disease and fibrosis, less often pulm HTN

• GI: dysmotility, “watermelon stomach”• Renal: Scleroderma Renal Crisis: acute renal failure with abrupt

onset of HTN. UA reveals only mild proteinuria. • Cardiac• Musculoskeletal: arthralgias, puffy hands early on, carpal tunnel• + ANA: often speckled pattern

Raynauds

Puffy hand stage

SS Clinical Intervention

• No single disease modifier. Instead treatment is aimed at the organs involved:– ACE inhibitors for renal protection– Calcium channel blockers for Raynaud’s– Promotility agents for GI – Cyclophosphamide debatable for lung disease,

Viagra/Levitra and Bosantan for pHTN– AVOID high dose steroids; can lead to renal crisis

SS Clinical Course

• Variable. Early stages: Raynaud’s, puffy hands, fatigue malaise, arthalgias/myalgias. Patients can also present with dyspnea +/- GI symptoms

• Poor prognosis with pulmonary involvement and rapid progression. Use of ACE inhibitors has improved renal outcomes.

CREST Syndrome

• AKA Limited Scleroderma• Calcinosis• Raynaud’s• Esophageal Dysmotility• Sclerodactyly of the fingers to the MCPs• Telangiectasia

Calcinosis

CREST Clinical Course

• Tends to be more benign than Systemic Sclerosis

• Complication: pulmonary HTN- get annual PFTs/DLCO

• Treat symptomatically

POLYMYOSITIS/DERMATOMYOSITS

• Autoimmune inflammatory myopathy resulting in painless muscle weakness +/- rash

• DM is often associated with an underlying malignancy in adults but not in children

• Rare: 2-10/100,000, more common in females• Peak ages 40-60 yo

Clinical Manifestations

• Painless muscle weakness of the proximal muscle groups with gradual onset. Patients will complain that they have difficulty getting out of a chair, climbing stairs, styling their hair due to lack of power

• Early on no signs of fasiculations or muscle atrophy

Skin Manifestations of DM

• Heliotrope rash of eyelids• Gottren’s papules on hands• Shawl sign• Mechanic hands• Periungal erythema• Calcinosis cutis

Heliotrope Rash

Gottron’s Papules

Shawl Sign

Mechanic’s hands

Periungual Involvement

Other Manifestations

• Pulmonary: Interstitial Lung Disease, BOOP, diffuse alveolar damage

• Esophagus: dysphagia and gagging• Misc: fever, polyarthritis, Raynaud’s• + ANA plus other autoantibodies• Elevated CPK. Aldolase, AST and ALT may also

be elevated

Diagnostic Tools

• EMG• MRI• Muscle Biopsy• Additional imaging if suspect malignancy

Treatment

• High dose corticosteroids• Methotrexate or Azathioprine• IV Ig for refractory/severe cases• If malignancy present, focus treatment on it

DM with resolve

Sjogren’s Syndrome

• Autoimmune disease affecting the exocrine glands causing dry eyes and dry mouth (sicca)

• Cause unknown. • Classified as primary or secondary (often seen

with rheumatoid arthritis or SLE)• Rare: incidence ~5/100,000• Female to male ratio 20:1; peak age 30-40

SjS Pathophysiology

• Trigger unknown. Infiltration of lymphocytes to the glands and are activated. Cytokines are released and promote parotid swelling, destruction and localized inflammation. B cells produce autoantibodies (SSA and SSB) and over time can transform from a benign polyclonal expansion to malignant expansion of lymphocytes resulting in lymphoma

SjS Clinical Presentation

• Sicca Symptoms: Dry eyes and dry mouth. Ask if the patient can cry or chew a saltine without any water.

• Parotid Swelling• Rash less common. Purpura of the lower

extremities• Complications: Lymphoma & Primary Biliary

Cirrhosis. Locally, accelerated dental caries, corneal atrophy and ulceration, oral candiasis

Parotid Swelling

SjS Diagnostic Studies

• + Rheumatoid Factor and ANA > 90%• + anti SSA 70-90%, anti SSB in 50%• Elevated ESR in the face of a normal CRP• + Shirmer’s test: strip of paper left in the

corner of patient’s eye against the cornea. Wetness at 5 minutes should be >10mm

• Biopsy of salivary gland not often performed as treatment is usually symptom based

Shirmer’s Test

SjS Treatment

• Dry mouth: good hydration. Frequent dental visits (q3m), avoid medications that make symptoms worse. Salagen or Evoxac can be beneficial but not usually earth-shattering

• Dry eyes: Artificial tears, lacrimal duct plugs, Restasis eye drops