2014 - Other Colagenosis - SSc

DIFFUSE CONNECTIVE TISSUE DISEASES4th year, General Medicine, 2014

DIFFUSE CONNECTIVE TISSUE DISEASES

SYSTEMIC LUPUS ERYTHEMATOSUS : SLE

SCLERODERMA ( scleroderma : Scl)

POLIMYOSITIS (PM) DERMATOMYOSITIS (DM)

RHEUMATOID ARTHRITIS (RA)

SJGREN SYNDROME :6.1 primary6.2. secondary : usually associated with each of the five connective tissue diseases/ collagen diseases

DIFFUSE CONNECTIVE TISSUE DISEASES

OVERLAP SYNDROME : collagen disease with an intricate simptomatology (RA, SS, SLE)present in 25% cases of the patients

Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic, multisystem disease of unknown etiology characterized by autoimmunity and inflammation, functional and structural abnormalities in small blood vessels, and progressive fibrosis of the skin and visceral organs

Scleroderma is usually divided into twomain forms, and then further subdivided

Morphea : leg

Linear scleroderma: thigh and leg

EPIDEMIOLOGYSystemic sclerosis, an acquired, sporadic disease with worldwide distribution, affects all races.

Estimates of its incidence in the United States range from 9 to 19 cases per million per year. Prevalence rate estimates range from 28 to 253 cases per million.

SSc is more common in females, with women-to-men ratios of 3 to 5 : 1.

ETIOLOGYGENETIC FACTORS

Some SSc patients (1.6%) have a fi rst-degree relative with the disease [relative risk (RR) = 13], indicating an important genetic contribution to disease susceptibility.

Genetic investigations in SSc havefocused on polymorphisms of candidate genes, particularly those involved in regulation of immunity and inflammation, vascular function, and connective tissue homeostasis.

ETIOLOGYENVIRONMENTAL FACTORS

The relatively low rates of twin concordance for SSc suggest the importance of environmental factors in disease susceptibility.

Among environmental factors, infectious agents (particularly viruses), exposure to environmental and occupational toxins (silica, polyvinyl chloride, aromatic hydrocarbons) and drugs (bleomycin, pentazocine, cocaine, and appetite suppressants - derivatives of fenfluramine) have been suspected of playing a role in the etiology of SSc.

The occurrence of SSc in some women with silicone breast implants raised concern regarding a possible association, but careful epidemiologic investigations found no evidence of increased risk of SSc

PATHOLOGY

An integrated view of the pathogenesis of SSc must incorporate :

the development of vasculopathy, activation of the cellular and humoral immune responses, progressive fibrosis (fibroblast activation) of multiple organs

PATHOLOGY

Autoimmunity, altered endothelial cell function, and vascular reactivity may be the earliest manifestations of SSc, leading to Raynauds phenomenon years before other disease features are present. Complex interplay among these processes initiates, amplifies, and sustains aberrant tissue repair and fibrosis.

Scleroderma: Raynauds phenomenon, blanching of hands

PATHOLOGYThe distinguishing pathological hallmark of SSc is an obliterative vasculopathy of small arteries and arterioles, combined vascular and interstitial fibrosis in target organs.

The organs most prominently affected by obliterative vasculopathy are the heart, lungs, kidneys, and intestinal tract.Fibrosis is prominent in the skin, lungs, gastrointestinal tract, heart, tendon sheath, perifascicular tissue surrounding skeletal muscle, and in some endocrine organs, such as the thyroid gland.

Clinical FeaturesRaynauds Phenomenon

Reversible vasospasm of digital vessels Occurs in more than 90% of people with SSc. Associated with color changes of the skin of the digits. Attacks triggered by cold temperature or emotional stress.Tissue damage May be seen in patients with chronic or severe Raynauds resulting in :tissue fibrosis of the fingers (sclerodactyly), loss of tissue from the digital pads (digital pitting),digital ulceration,and on occasions, ischemic demarcation and the need for digital surgery or amputation.

Scleroderma: Raynauds phenomenon, blanching of hands

Scleroderma: Raynauds phenomenon, cyanosis of the hands

A, B) Digital ulcers and digital gangrene are caused by severe degrees of ischemia.

Digital ulcers are caused by severe degrees of ischemia

Digital gangrene are caused by severe degrees of ischemia

Clinical FeaturesSkin

The hallmark feature of SSc is thickened skin

Early changes In the earliest stage of disease, the skin appears mildly inflamed with nonpitting edema and, in some cases, erythema, and pruritus.Over time, collagen deposition leads to thickening of the dermis, with gradual damage to the normal skin and its appendages. The patient notices tightening of the skin and decreased flexibility. Late changes As SSc progresses into the fibrotic stage, the skin becomes more thickened, and severe drying of the surface often leads to pruritus. The skin then becomes atrophic and thinned, with tethering secondary to the binding of fibrotic tissue to underlying structures.

Scleroderma: edematous changes, hands

Scleroderma: skin induration, hands

Scleroderma: acrosclerosis and terminal digit resorption

Metacarpophalangeal ulcers are due to poor perfusion in areasof stretched skin or in areas of repeated minor trauma.

Clinical FeaturesSkin

Skin manifestations also include hyper- and/or hypopigmentation, telangiectasias, calcinosis, dermal ulcers, digital tip pitting scars, and digital tip gangrene

Scleroderma: Mauskopf, facial changes

Telangiectasias most commonly occur over the fi ngers, palms,dorsum of the hands, and face.

Scleroderma: Mauskopf, facial changes

CREST syndrome: calcinosis cutis, fingers

Calcinosis can occur in the hands as well as in the forearms,elbows, knees, and legs.

Metacarpophalangeal ulcers are due to poor perfusion in areasof stretched skin or in areas of repeated minor trauma.

Digital gangrene are caused by severe degrees of ischemia

Clinical Features gastrointestinal manifestations

Next to skin involvement, the GI system is most commonly affectedGastrointestinal symptoms are related to dysmotility which, in turn, is related to smooth muscle atrophy and fibrosis

Mouth A small oral aperture, dry mucosal membranes, and periodontal disease (Sjogrens syndrome) can lead to problems with chewing foods, loss of teeth, and poor nutrition.

Upper esophagus Dysphagia and heartburn are the most common gastrointestinal symptoms found in SSc.

Lower esophagus Esophageal disease is associated with esophageal reflux (GERD), esophagitis, and delayed emptying of the stomach, leading to early satiety, bloating, nausea, and vomiting.

Scleroderma: abnormal motility, esophagus (radiograph)Isenberg DA, Renton P, Imaging in Rheumatology, 2003

Clinical Features gastrointestinal manifestations

Small intestine Dysmotility of the small intestine may be asymptomatic, or it can cause severe distension, abdominal pain, and vomiting. Mild abdominal distension, crampy abdominal pain, diarrhea, weight loss, and malnutrition also can be consequencesof malabsorption caused by bacterial overgrowth in stagnant intestinal fluids.

Large intestine As a consequence of muscular atrophy of the large bowel wall, asymptomatic wide-mouth diverticula unique to SSc commonly are found in the transverse and descending colon.

Primary biliary cirrhosis (PBC) occurs in a small proportion of patients but at a rate that is greater than expected in the general population

Scleroderma: wide-mouthed diverticula, colon (radiograph)

Clinical Features MusculoskeletalCharacteristics of musculoskeletal involvement include (1) :

Joint contractures (due to involvement of overlying skin) and restricts motionThe hands, wrists, and elbows are the most commonly affected joints Range of motion may also be reduced at the shoulders, hips, knees, and anklesTendon friction rubsthe most commonly affected tendon sheaths are those of the ankle dorsifl exors, the fi nger extensors, and the knee extensorsMyopathy, myositis : mild proximal muscle weakness;normal or slight elevations of creatine phosphokinase (CPK);poor response to corticosteroidsthe dominant musculoskeletal problem in late SScis muscle atrophy and weakness

Clinical Features Musculoskeletal

Characteristics of musculoskeletal involvement include (2) :

Bone resorptionOsteolysis or bone resorption of the digital tufts, seen in 40% to 80% of patients, is believed to be on the basis of chronic ischemia Synovitis : the arthritis of SSc is nonerosiveCompression neuropathies : The most common compression neuropathy in SSc is carpal tunnel syndrome

PULMONARY AND PULMONARYVASCULAR DISEASE

Pulmonary disease is now the leading cause of death in SSc

Patients with dcSSc are at higher risk of developing significant lung fi brosis compared to those with lcSSc

Early lung disease is frequently asymptomaticdry cough, dyspnea on exertiona are later symptoms

PULMONARY AND PULMONARYVASCULAR DISEASE

Pulmonary function test that show a restrictive pattern is the most sensitive test for pulmonary parenchymal diseasedecreases in the vital capacity, lung volumes, and/or diffusing capacity for carbon monoxide (DLCO) are indicative of restrictive changes.

An isolated decrease in DLCO may also indicate pulmonary hypertension.

Computed tomography (CT) scans of the lung are more sensitive than radiographs for the detection of early fibrotic changes

PULMONARY AND PULMONARYVASCULAR DISEASE

The prevalence of PAH in the SSc patient population when measured by right heart catheterization is 8% to 12%

The prevalence of PAH by echocardiogram alone is more than double and emphasizes the point that right heart catheterization is necessary to confirm the diagnosis

Pulmonary hypertension can occur on the basis of two main pathologic processes: (1) those primarily involving destruction or obliteration of lung vasculature, such as pulmonary fibrosis, recurrent thromboembolic disease, or scleroderma vasculopathy; (2) those associated with decreased cardiac output, for example, diastolic dysfunction, congestive heart failure, or valvular disease.

Pulmonary arterial hypertension (PAH) is a term used to describe the first group of conditions

RENAL DISEASE ANDSCLERODERMA RENAL CRISIS

Scleroderma renal crisis (SRC) was the most common cause of death in SSc prior to the introduction of angiotensin -converting enzyme (ACE) inhibitors

SRC still occurs, typically in the setting of early diffuse disease (

Laboratory Features

Routine studies Routine chemistries and complete blood count should be obtained at baseline and at follow-up as necessary

Antinuclear antibodies Positive in most patients, typically in a speckled pattern. Specific antinuclear antibodies (anticentromere, antitopoisomerase anti Scl 70 -, and RNA polymerase, etc.) may be seen in subsets of SSc patients and help to predict the risk of future organ involvement and course.

Diagnosis

KEY CLINICAL FEATURES OF SYSTEMIC SCLEROSISDiffuse cutaneous systemic sclerosis (dcSSc)

Proximal skin thickening involving the trunk, upper arms and thighs, in addition to symmetrical involvement of the fi ngers, hands, arms, and face/neckRapid onset of disease following the appearance ofRaynauds phenomenonSignificant visceral disease: lungs, heart, gastrointestinal, and/ or kidneysAbsence of anticentromere antibodiesVariable disease course but overall poor prognosis, with survival 40% to 60% at 10 yearsLimited cutaneous systemic sclerosis (lcSSc)Symmetrical skin thickening limited to the areas below the elbows and knees and involving the face/neckProgression of disease typically months or years after the onset of Raynauds phenomenonLater and less severe development of visceral diseaseLate development of pulmonary arterial hypertensionAssociation with anticentromere antibodiesRelatively good prognosis with survival >70% at 10 years

Overlap syndromesDiffuse or limited systemic sclerosis with typical features of one or more of the other defi ned connective tissue diseases Mixed connective tissue disease: features of systemic lupus erythematosus, systemic sclerosis, and polymyositis in the presence of anti-U1 RNP antibodies

Treatment

Scleroderma: pulmonary fibrosis (radiograph)

Isenberg DA, Renton P, Imaging in Rheumatology, 2003 FIBROZA PULMONARA >>>>>>>>>>>>>>>>>>>>>>>

Isenberg DA, Renton P, Imaging in Rheumatology, 2003

Scleroderma: acrolysis (radiographs)

Scleroderma: calcinosis and acrolysis (radiograph)

Idiopathic InflammatoryMyopathies

Idiopathic inflammatory myopathies (IIM) is a heterogeneous group of disorders characterized by chronic inflammation of striated muscle and skin.

Painless proximal muscle weakness with or without rash is the hallmark feature

Increased serum muscle enzymes, muscle biopsy, electromyography (EMG), and magnetic resonance imaging (MRI) can assist in the diagnosis.

Idiopathic InflammatoryMyopathies

Idiopathic Inflammatory MyopathiesEpidemiology

The idiopathic inflammatory myopathies are relatively rare diseases:estimates of prevalence range from 0.5 to 9.3 cases per million

The age at onset of the idiopathic inflammatory myopathies has a bimodal distribution, with peaks between ages 10 and 15 years in children and between 45 and 60 years in adults.

Both myositis associated with malignancy and IBM are more common after the age of 50 years.

Female predominance is especially great between the ages of 15 and 44 years, in myositis associated with other collagen-vascular diseases, and in blacks

Idiopathic Inflammatory MyopathiesPathogenesis

Etiology is still unclear but selected environmental exposures in genetically predisposed hosts have been found

Genetic FactorsPolymorphic alleles in the major histocompatibility locus (MHC) are the major immunogenetic risk and protective factors identified for the IIMEnvironmental FactorsThe infectious agents : Group A streptococcus and influenza have the strongest evidence of association with onset of juvenile IIM and toxoplasmosis with adult DM from case-controlled epidemiologic studiesNoninfectious agents : ultraviolet light, physical exertion, psychological stress, medications, and vaccines, collagen implants

Idiopathic Inflammatory MyopathiesClinical Features

The dominant clinical feature of the idiopathic inflammatory myopathies is symmetric proximal muscle weakness The weakness initially affects the muscles of the shoulder and pelvic girdle Weakness of neck muscles, particularly the flexors, occurs in about half the patients

Pharyngeal muscle weakness may cause dysphonia and difficulty in swallowing

Idiopathic Inflammatory MyopathiesClinical Features

PM is a systemic disease, and patients may develop morning stiffness, fatigue, anorexia, weight loss, and fever. If weight loss persists or is severe, an associated malignancy should be considered Arthralgias are not uncommon, but frank synovitis is less usual

Pulmonary and cardiac manifestations may occur at any time during the course of the disease Interstitial pneumonitis may cause dyspnea, a nonproductive cough, hypoxemia, and fatal respiratory failure Cardiac involvement is usually absent or is restricted to electrocardiographic abnormalities. However, heart block, supraventricular arrhythmia, or cardiomyopathy may develop, causing syncope, palpitations, or congestive heart failure

Idiopathic Inflammatory MyopathiesClinical FeaturesSkin

The clinical features of DM include all those described for PM plus cutaneous manifestations

The skin rash of dermatomyositis may precede, develop simultaneously with, or follow symptoms of myopathy

Gottrons papules Mechanics handsPhotosensitivity withRash on the face or anterior chest, termed the V signRaynauds phenomenon.

Papule Gottron

Malignancy and MyositisRecent reports strongly support an increased risk of cancer in patients with polymyositis and an even greater risk with dermatomyositis.

The overall risk of cancer is greatest in the fi rst 3 years after the diagnosis of myositis, but an increased risk of malignancy persists through all years of follow-up, emphasizing the importance of continued surveillance.

The strongest associations are with ovarian, lung, pancreatic, stomach, and colorectal cancer and with non-Hodgkins lymphoma.

INVESTIGATIONSSerum Muscle EnzymesEnzymes that leak into the serum from injured skeletal muscle include the CK, aldolase, AST, ALT, and LDH

ElectromyographyElectromyography is a sensitive but nonspecific method of evaluating muscle for evidence of infl ammationEMG, about half show the classic fi ndings of inflammation of fibrillation potentials, complex repetitive discharges, positive sharp waves, and complex motor unit potentials of low amplitude and short duration

Muscle BiopsyMuscle histology remains the gold standard for confirming the diagnosis of an IIM

INVESTIGATIONSMRI is noninvasive and can be used to visualize large areas of muscleHRCT (high resolution CT) and chest radiographsPulmonary function testing

Serum AutoantibodiesANAAntiJo 1 antibodies are directed against histidyl-tRNA synthetase

Pharmacologic TherapyCorticosteroids :

Start : 60 mg/day of prednisoneafter normalization of the serum CK (often within 13 months), the prednisone can be consolidated to a once-daily dose and tapered by approximately 20% to 25% of the existing dose every 3 to 4 weeks to a daily morning dose of 5 to 10 mg. this dose should be maintained for several months depending on the clinical course, but patients often flare, necessitating an increase of CS to a previously effective (but not necessarily initial) dose.

Pharmacologic TherapyOther Immunosuppressive AgentsMethotrexate or azathioprine are often the first IS, steroid-sparing agents chosen and their combination has proven efficacious in refractory myositis

Extramuscular Manifestations