Isther
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A 26 yo F. Presents referring difficulty swallowing and heart burn. Family and personal history are unremarkable. Currently under no medication. On PE the patient is in no distress, skin creases are absent in the face, and the distal part of the fingers are bluish. VS are normal. She is evaluated by specialists and proper treatment is prescribed. Two weeks later the patient returns complaining that even that she feels different from before, she doesn´t feel good. She presents with a cutaneous rash, and sore lesions in her mouth. BP 130/75, PR 100, RR 18, Tº 98ºF. Urine analysis presents no protein, RBC, WBC or casts. What would be the proper thing to do next?
- Renal biopsy
- Order ANA, anti-SM, anti-ds DNA.
- Start a high-dose steroids trial
- Order anti-histones
- Increase the dose of the medication
- Reassurance and discharge
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| AAAAA
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Scleroderma is a disease that causes thickened skin and varying degrees of organ dysfunction resulting from small-vessel vasculopathy and immune-mediated fibrosis. The clinical manifestations of this disease are extremely heterogeneous and depend on the presence and degree of internal organ involvement. Patients may present with a spectrum of illness ranging from localized skin fibrosis only (localized scleroderma) to a systemic disorder (systemic scleroderma) with both cutaneous and internal organ involvement.
Localized scleroderma includes various forms of cutaneous sclerosis without internal organ involvement (Table 1). These forms of scleroderma can be disfiguring but only rarely require systemic therapy to control disease activity.
Systemic scleroderma is further divided into two subsets of disease, depending on the degree of skin and organ involvement (Table 1). Diffuse cutaneous systemic sclerosis (dcSSc) denotes the presence of extensive cutaneous sclerosis over the proximal limbs, trunk, and face. Patients with limited cutaneous systemic sclerosis (lcSSc ) have fibrosis limited to the hands and even the face. Both dcSSc and lcSSc are associated with internal organ involvement; however, patients with dcSSc are at greater risk of clinically significant major organ dysfunction. Some patients with lcSSc may be further classified as having the CREST syndrome, with accompanying calcinosis, Raynaud's phenomenon (RP), esophageal dysmotility, sclerodactyly, and cutaneous telangiectasias. Scleroderma sine sclerosis is a rare disorder in which patients develop vascular and fibrotic damage to internal organs in the absence of cutaneous sclerosis.
EPIDEMIOLOGY
Systemic scleroderma is a rare disorder, with an annual incidence in the United States of 19.3 cases per million adults.1 Several studies have estimated the prevalence of systemic sclerosis in the United States to be around 250 cases per million adults.2 International reports from Britain and Japan report a lower prevalence, of around 35 cases per million persons.2 Women are roughly four times more likely than men to develop systemic scleroderma. Additionally, blacks are more commonly affected than whites and are at greater risk for diffuse disease.1 Most patients with systemic scleroderma present after the third or fourth decade of life.
Age- and gender-adjusted mortality rates for patients with dcSSc are approximately five to eight times greater than those of the general population.3 Survival has improved over the past few decades, and is strongly dependent on the degree of organ involvement. Renal and pulmonary diseases are the major causes of mortality. Patients with dcSSc have poorer survival than those with lcSSc.1 However, patients with lcSSc and pulmonary hypertension also have a poor overall prognosis.
PATHOPHYSIOLOGY
Scleroderma is characterized by immune system activation, endothelial dysfunction, and enhanced fibroblast activity. The precise inciting events leading to the development of systemic scleroderma are currently unknown. Most experts believe that the effector cell is the activated fibroblast.4 Several cytokines including interleukin-2 and transforming growth factor-beta (TGF-ß) have been implicated in fibroblast activation in patients with scleroderma. These cytokines are released from activated immune cells, fibroblasts, and endothelial cells.4 Activated fibroblasts elaborate structurally normal collagen and other extracellular matrix proteins in the skin and various internal organs.5
Vascular injury occurs even before clinically obvious fibrosis; indeed, RP is often the earliest clinical finding in patients who eventually develop systemic scleroderma. Most damage occurs at the level of the cutaneous circulation and in the microvasculature of various internal organs4 The vascular injury is believed to originate at the level of the endothelial cells. Small arteries and capillaries constrict, with eventual obliteration of the vessel lumen and ensuing ischemia.
CLINICAL MANIFESTATIONS
Clinical manifestations of systemic scleroderma are heterogeneous and vary as a result of type of disease (limited or diffuse) and organ involvement (Table 2). Patients with diffuse skin changes (dcSSc) are at risk for rapidly progressive skin fibrosis and widespread, severe, internal organ involvement. Patients with limited disease (lcSSc) have a disease course characterized by slowly progressive skin changes not extending beyond the elbows and knees into the proximal extremities or trunk, along with varying degrees of internal organ involvement.
RP is present in most patients with systemic scleroderma and is often the earliest manifestation of disease. RP may be present for years before clinically significant skin changes or internal organ involvement develops. Although some patients with RP may not develop the entire spectrum of Raynaud skin changes,4 most will have digital pallor in response to cold or stress.
Cutaneous changes usually begin with an early phase of skin edema, manifested as swollen fingers and hands. In dcSSc, these changes are followed by the development of firm, thickened skin over the extremities, trunk, face, and hands. The patients in whom these changes develop more rapidly are at greater risk for serious internal organ involvement such as pulmonary fibrosis and renal failure. Skin changes typically peak before the first 5 years.6 As a result of skin thickening, flexion contractures can develop over joints. Skin thickening may then begin to regress, as manifestations of internal organ involvement become more clinically evident. In patients with lcSSc, early skin changes include RP and digital ulceration. Skin thickening and digital edema are confined to the distal extremities (beyond the elbows and the knees). As the disease progresses, there is an increase in cutaneous telangectasias, calcinosis, and digital ischemia.
Patients may complain of dyspnea or nonproductive cough as a manifestation of underlying pulmonary disease. Some patients may be asymptomatic but manifest changes on chest radiography (lower-lobe interstitial infiltrates) or physical examination (basilar rales). Lower-extremity edema and other signs or symptoms of right-sided heart failure may also lead to suspicion of pulmonary hypertension. Pulmonary function tests are frequently abnormal, revealing restrictive changes even in the absence of radiographic changes or exertional dyspnea. Patients with dcSSc are more likely to develop interstitial lung disease, and a subset of patients with lcSSc can develop a severe form of pulmonary arterial hypertension without interstitial lung disease. In patients with either form of systemic scleroderma, symptomatic pulmonary disease is a relatively uncommon finding in the first few years of disease. However, patients with dcSSc and rapidly progressive skin changes or anti-topoisomerase antibodies (anti-Scl-70) are at risk for earlier onset of severe pulmonary disease.7
Scleroderma renal crisis is characterized by the development of severe hypertension, renal insufficiency, and microangiopathic hemolytic anemia. A small subset of patients may be normotensive at diagnosis.8 Patients with rapidly progressive diffuse skin fibrosis, users of glucocorticoids, or those with large, chronic pericardial effusions are at greatest risk. The development of renal crisis is rare in patients with lcSSc, and most cases occur in the first few years of dcSSc. Renal failure can follow a rapidly progressive course, and early recognition and treatment with angiotensin-converting enzyme inhibitors is critical.
Gastrointestinal involvement is common in both forms of systemic scleroderma. Atrophy of the muscularis mucosa and submucosal fibrosis result in varying degrees of esophageal and other gastrointestinal dysfunction. Complaints of dysphagia and heartburn are common and often signal the development of esophageal dysmotility. Esophageal disease can progress, resulting in peptic esophagitis, esophageal strictures, and eventual development of an atonic esophagus. Gastric telangiectasia (watermelon stomach) can lead to chronic upper gastrointestinal bleeding and iron deficiency anemia. Small-bowel motility may also be affected, resulting in varying degrees of malabsorption and bacterial overgrowth. Severe constipation may develop from colonic hypomotility. Gastrointestinal bleeding is infrequent, but may occur from erosive esophagitis, wide-mouth diverticula in the colon, and gastritis. Pneumatosis cystoides intestinalis can present as an acute abdomen. Patients with lcSSc may also develop primary biliary cirrhosis.
Cardiac involvement is rare in lcSSc, but myocardial fibrosis may develop in patients with dcSSc, resulting in heart failure, arrhythmias, and atrioventricular conduction defects. Other features of systemic scleroderma may include dry eyes and mouth (secondary to Sjögren's syndrome) and hypothyroidism (Hashimoto's thyroiditis). Musculoskeletal involvement is common and may present as nonspecific myalgias and arthralgias or true arthritis. Muscle weakness may also occur in the presence of elevated serum levels of muscle enzymes.
DIAGNOSIS
The diagnosis of systemic scleroderma is usually made on the basis of the characteristic cutaneous finding of skin thickening in association with RP and various degrees of internal organ involvement. In early disease, RP may be the dominant cutaneous finding. Examination of the nailfold capillaries with capillaroscopy may be helpful in determining whether RP is due to primary disease or secondary to a systemic disorder such as scleroderma.9 Other disorders associated with scleroderma-like skin changes, such as eosinophilic fasciitis and eosinophilia-myalgia syndrome, are not typically associated with RP.
Diagnostic criteria were proposed by the American College of Rheumatology (formerly known as the American Rheumatism Association)10 for studying patients in different centers (Table 3). However, there are limitations regarding their usefulness, especially for lcSSc, and experts have recommended9 some modifications to the original criteria.
Serologic testing for autoantibodies can be helpful in the diagnosis and classification of systemic scleroderma.11 However, none of the serologic tests is sensitive enough to independently exclude disease. The presence of anticentromere (ACA) and anti-Scl-70 antibodies has been described in patients with systemic sclerosis. ACAs are found in roughly 60% of patients with lcSSc and only rarely in patients with dcSSc. Antibodies to topoisomerase-1 are present in 40% of patients with dcSSc. The presence of either ACAs or anti-Scl-70 is highly specific (95% to 99%) for the diagnosis of lcSSc and dcSSc, respectively. The antibodies are present only rarely in healthy subjects and patients with other rheumatologic disease. The presence of ACA or anti-Scl-70 antibodies is also highly specific for underlying systemic sclerosis in patients presenting initially with isolated RP12 and therefore may be helpful in the evaluation of RP.
Once the diagnosis has been established, the clinician must determine whether the disease is diffuse or limited. The degree of organ involvement must also be determined by physical examination, history, laboratory markers, and various radiologic studies. The extent of skin thickening must be carefully documented in all follow-up visits.
Complaints of dysphagia, early satiety, nausea/vomiting, or heartburn should be investigated with esophageal manometry and endoscopy (although in practice these invasive studies are often not done unless there is a reason to suspect esophageal stricture, Barrett's esophagus, or adenocarcinoma). Pulmonary function studies, including diffusion capacity for carbon monoxide (DLCO), may confirm the presence of restrictive lung disease. An isolated or disproportionate reduction in DLCO compared with forced vital capacity and total lung capacity may raise the suspicion of pulmonary hypertension. Chest radiography and high-resolution computed tomography may suggest the presence of interstitial lung disease and help differentiate active alveolitis (ground-glass appearance) from established pulmonary fibrosis (honeycombing). Surface echocardiography and right-heart catheterization are necessary to evaluate and confirm the presence of pulmonary hypertension. To investigate the possibility of renal crisis, tests of renal function, urinalysis, and peripheral blood smear are necessary in all patients with new or worsening hypertension, renal insufficiency, or new anemia in the absence of blood loss.
TREATMENT AND ASSESSMENT
OF DISEASE ACTIVITY
Institution of therapy is predicated on proper assessment of disease activity and organ involvement. The extent of skin thickening is useful for assessing overall disease activity, disease subset (lcSSc or dcSSc), prognosis, and risk of internal organ involvement.6 Valentini et al described a disease activity index for systemic sclerosis and a separate but similar index for the individual subsets of dcSSc and lcSSc.13 Subjective changes reported by the patient in cardiopulmonary, skin, muscular, joint, or vascular disease were most predictive of disease activity in dcSSc. Diffusion studies for carbon monoxide were also useful. In addition to subjective changes in cardiopulmonary, vascular, and skin involvement, hypocomplementemia and erythrocyte sedimentation rate >30 mm in the first hour were also predictive of disease activity in patients with lcSSc.13
Although no therapy has been proven to reverse the vascular and fibrotic damage in patients with scleroderma, several therapies are available in an effort to slow disease progression, improve vascular function, limit mortality, and provide supportive symptomatic care.
RP is treated with cessation of smoking, avoidance of cold exposure, use of warm clothing and gloves, avoidance of vasoconstrictive substances (clonidine, sympathomimetics, cocaine, ergotamines), and various pharmacologic agents aimed at reversing digital vasospasm. The dihydropyridine calcium channel blockers (amlodipine and nifedipine) are first-line agents for the treatment of scleroderma-associated RP.14 Sustained-release preparations are preferred, and the dose should be adjusted to reduce the severity and frequency of attacks. Patients should be monitored for dose-limiting side effects such as worsening of reflux symptoms, lower extremity edema, headache, flushing, and hypotension. Iloprost, an intravenous prostaglandin not available in the United States, has also been shown to ameliorate RP and improve digital ulceration. For patients who do not respond to calcium channel blockers, other drugs such as nitrates, hydralazine, and prazosin may be tried. The role of antiplatelet and anticoagulant therapy is unclear, although in the absence of contraindications, most experts would recommend low-dose aspirin to all patients with RP. Endothelin receptor antagonists (such as bosentan) are being studied for their ability to counter vasoconstriction and promote vessel remodeling.14
Patients with RP and critical digital ischemia require hospitalization, pain relief, intravenous vasodilator therapy, systemic anticoagulation14 and, in the presence of concomitant infection, systemic antibiotics. Angiographic assessment may be necessary to evaluate for the presence of large-vessel disease, and digital sympathectomy may be necessary to inhibit sympathetic-mediated vasoconstriction.
Because of its anticollagen and immune-modulating effects, D-penicillamine has been used in patients with dcSSc in an effort to slow skin fibrosis. The effect of the drug is often slow in onset (several months). Although some small observational studies have demonstrated a small benefit in 5-year mortality and a decrease in development of visceral disease, the role of D-penicillamine remains unclear. Clements et al did not show an advantage of high-dose D-penacillamine over low-dose D-penacillamine therapy, and patients in the high-dose arm had a higher withdrawal rate as a result of adverse events.15
Cyclophosphamide may be beneficial in patients with interstitial lung disease associated with scleroderma.16 Methotrexate has been shown to improve skin scores and diffusion capacity.17 Ideally, these agents would have optimal benefit in the earlier stages of disease before severe cutaneous and visceral fibrosis have occurred. Corticosteroids may be useful in the treatment of myositis and alveolitis, but the use of corticosteroids is limited by the observation that high doses may precipitate renal crisis.8 Immunoablation combined with autologous stem cell rescue is still considered experimental, but one report documented improved skin disease.18 However, 1-year mortality was high after transplant.18
Gastroesophageal reflux is treated with proton pump inhibitors, and motility disorders are treated with prokinetic agents such as metoclopramide and domperidone. Small-bowel malabsorption and diarrhea caused by bacterial overgrowth may respond to chronic, alternating regimens of antibiotics. Endoscopy-directed dilatation may be necessary in cases of esophageal stricture leading to dysphagia, and in gastric bleeding from ectatic vessels.
Angiotensin-converting enzyme inhibitors should be used at the first sign of hypertension, microangiopathic hemolytic anemia, or unexplained renal insufficiency. Their early use is critical in preserving renal function, controlling hypertension, and improving survival during renal crisis. In the hope that control of renin-mediated hypertension may result in renal recovery, therapy with angiotensin-converting enzyme inhibitors should be continued even in the face of renal insufficiency requiring dialysis.19
Interstitial lung disease and alveolitis may be treated with cyclophosphamide and extended courses of prednisone.20 Pulmonary hypertension is treated with oxygen (in the presence of hypoxia) and vasodilators such as calcium channel blockers or prostacyclin analogs. Epoprostenol is an intravenous prostacyclin analog delivered by continuous central infusion. In limited trials, it has been shown to improve functional status and RP.21 Iloprost and treprostinil are newer synthetic prostacyclins delivered by inhaled and subcutaneous routes, respectively. Bosentan is an oral endothelin receptor antagonist that may improve functional status in patients with pulmonary arterial hypertension and systemic scleroderma or systemic lupus erythematosus.22 Some experts recommend long-term anticoagulation for patients with scleroderma and pulmonary hypertension.3,16
FUTURE DIRECTIONS
The central role of TGF-ß in inducing endothelial damage and fibroblast activation has led investigators to target this molecule as a promising site for future therapies. Indeed, anti-TGF-ß drugs and other cytokine-based therapies could theoretically provide true disease modification, especially in patients with early disease, before cutaneous and internal fibrosis have resulted in significant irreversible damage.23
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| AAAAA
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Q: On PE the patient is in no distress, skin creases are absent in the face, and the distal part of the fingers are bluish.
Patients with limited cutaneous systemic sclerosis (lcSSc ) have fibrosis limited to the hands and even the face. Both dcSSc and lcSSc are associated with internal organ involvement; however, patients with dcSSc are at greater risk of clinically significant major organ dysfunction. Some patients with lcSSc may be further classified as having the CREST syndrome, with accompanying calcinosis, Raynaud's phenomenon (RP), esophageal dysmotility, sclerodactyly, and cutaneous telangiectasias. Scleroderma sine sclerosis is a rare disorder in which patients develop vascular and fibrotic damage to internal organs in the absence of cutaneous sclerosis.
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| AAAAA
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Complaints of dysphagia and heartburn are common and often signal the development of esophageal dysmotility. Esophageal disease can progress, resulting in peptic esophagitis, esophageal strictures, and eventual development of an atonic esophagus.
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| AAAAA
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Serologic testing for autoantibodies can be helpful in the diagnosis and classification of systemic scleroderma.11 However, none of the serologic tests is sensitive enough to independently exclude disease. The presence of anticentromere (ACA) and anti-Scl-70 antibodies has been described in patients with systemic sclerosis. ACAs are found in roughly 60% of patients with lcSSc and only rarely in patients with dcSSc. Antibodies to topoisomerase-1 are present in 40% of patients with dcSSc. The presence of either ACAs or anti-Scl-70 is highly specific (95% to 99%) for the diagnosis of lcSSc and dcSSc, respectively. The antibodies are present only rarely in healthy subjects and patients with other rheumatologic disease. The presence of ACA or anti-Scl-70 antibodies is also highly specific for underlying systemic sclerosis in patients presenting initially with isolated RP12 and therefore may be helpful in the evaluation of RP.
Once the diagnosis has been established, t
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| AAAAA
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The presence of anticentromere (ACA) and anti-Scl-70 antibodies has been described in patients with systemic sclerosis.
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| AAAAA
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Diagnostic Tests: Anti-Smith Antibodies (Sm)
The Immunofluorescent Antinuclear Antibody test (ANA), is a blood test that is commonly used to evaluate patients who are suspected of having an autoimmune or connective tissue disorder. The ANA is a simple and extremely sensitive test which is positive in over 95% of SLE patients. However, as the test is not specific to SLE, other, more specific tests are often used to support a positive ANA result.
The anti-smith antibodies (Sm) test ismore specific and is used to confirm the diagnosis of lupus from an ANA. The anti-Smith (Sm) autoantibody response is highly specific for systemic lupus erythematosus (SLE).
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Brands:
Anti-Smith Antibodies (Sm)
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| AAAAA
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The Immunofluorescent Antinuclear Antibody test (ANA), is a blood test that is commonly used to evaluate patients who are suspected of having an autoimmune or connective tissue disorder.
I AM SOT SURE THE ANSWER BECAUSE ANA "MAY" BE USED TO TEST FOR CONNECTIVE TISSUE DISORDER AS IN THIS PATIENT BUT ACA ANTI-CENTROMERE AND ANTI-Scl-70 are more speciifc.
So are we given all the answers or best answers ?
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| AAAAA
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Two weeks later the patient returns complaining that even that she feels different from before, she doesn´t feel good. She presents with a cutaneous rash, and sore lesions in her mouth.
Answer 4 or D ???
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| monterusca2004
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Well, really I will go rather for scleroderma, however the test would be anti scl 70 antibodies, but they are not in the choices, and star therapy would not be correct before being sure what disease does she has.
Anti histone antibodies are for SLE induced by drugs, so that wouldnt be the answer either.
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| MAZI
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i will go for 3. high dose steroid
i think that this is the hypersensivity syndrom( steven jonson syndrom) because of initiation of drug (methotraxate or D- penicilamide) for treatment of sclorodermia
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| guayoman
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I agree with MAZI. Sounds like a whole new deal after the initiation of drugs.
What is the answer?
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| AAAAA
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"She presents with a cutaneous rash, and sore lesions in her mouth. "
Steven Johnson's Syndrome is a serious systemic disorder in which there are vesicobullous lesions involving the skin and mucous membranes. It can result as an immune response to an antigen or as a drug reaction. Most often it is considered as an allergic reaction. It is a self-limiting condition which responds to immediate management or may result in fluid loss, sepsis and death.
High dose steroid may be the answer if she indeed had Steven Johnson Syndrome !
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| drk1980
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good one MAZI!
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| Isther
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The answer is 4... anti-histones.
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| Isther
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The patient has a clear initial picture of CREST, one of the options for treatment is penicillamine for the skin manifestations.
Among the probable side effects of penicillamine are drug-induced lupus and steven johnson syndrome. Both may fall in the shallow description of rash and oral sores. The former will completely resolve with the discontinuation of the offending drug, steven johnson may improve with steroids, the differentiation must be done before high-dose steroids are administered, therefore, anti-histones will be the proper next step.
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| Isther
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The other options all incorrect.
Very nice explanation AAAAA, what is your source?
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| Isther
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This is the 3 steps type of question that I hate... time consuming and pain in the neck during the exam... First must diagnose CREST, then identify the probable treatment, and finally its side effects.
Hope you like it!
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| drk1980
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wow! totally pulled the rug.....good one Isther!!
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| cyra
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Great q Isther!
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