Basic semiology. However, emergency reasoning: systolic murmur, something that in systole had to be closed and is not, or had to open, and does not: options 1, 3 and 5. And if we see repercussion in the jugular pulse, it must be in the right cavities. Apart from the fact that the v wave appears during systole, while the atria are filling: if the RV flow rises to the RA, what will happen is that the v wave will be very large?

If in a patient with chronic heart failure we detect prominent v waves in the jugular venous pulse and on cardiac auscultation a holosystolic murmur is auscultated in the area of the xiphoid appendage that is accentuated with deep inspiration. What is the valvulopathy responsible for this physical examination?

Valvular heart disease

On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs. Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension.

Valvular heart disease

Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension. Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation Causes

Aortic regurgitation

If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic 'flow' murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes. Characteristics- indicative of aortic regurgitation are as follow:

[M-mode echocardiographic standardization of interventricular septal motion and its clinical significance].

Systolic and diastolic motions of the interventricular septum (IVS), especially of its lower portion at the level of the chordae tendineae, were evaluated by M-mode echocardiography in normal subjects and in patients with various cardiac disorders. The following conclusions were derived from this study. In normal subjects, downward motion of the IVS exhibited three patterns; namely, P1, between the onset of electrical depolarization and the onset of the second heart sound; P2, between the onset of the second heart sound and the E point of the anterior mitral leaflet; and P3, between the E point of the anterior mitral leaflet and the end of the left ventricular rapid filling phase, during each cardiac cycle. The systolic IVS pattern (P1) of atrial septal defect was classified as follows: Normal type: nearly normal posterior motion during ventricular systole, Flat type: flat motion during ventricular systole, Paradoxical (early systolic) type: anterior motion during the first half of ventricular systole, followed by normal posterior motion, Paradoxical (pansystolic) type: anterior motion during ventricular systole. In atrial septal defect, the right ventricular dimension was markedly increased in the flat and paradoxical (pansystolic) types compared with those of the normal and paradoxical (early systolic) types. Marked downward IVS motion (P2) was observed in cor pulmonale with paradoxical pulse, pulmonary hypertension, Ebstein's anomaly, pulmonic insufficiency, atrial septal defect, funnel chest, tricuspid insufficiency and constrictive pericarditis. In cor pulmonale with paradoxical pulse, the deep downward motion (P2) was observed more distinctly during inspiration compared to expiration, and right ventricular inflow velocity pattern was characterized by an apparent increase in peak flow in velocity of the diastolic rapid filling wave during inspiration. Two interesting findings were a deep "y" trough of the jugular pulse tracing and prominent P2 in funnel chest. Therefore, it was likely that exaggerated P2 seemed to be direct evidence of a marked increase in right ventricular rapid filling in the presence of normal or decreased left ventricular rapid filling. The augmented septal dip of P3 was observed in cases with the third heart sound as in normal subjects, and those with mitral insufficiency, and ventricular septal defect, constrictive pericarditis and mitral stenosis. We theorized that exaggerated P3 results from the "sucking action" secondary to increased left ventricular rapid filling velocity in cases with the third heart sound or constrictive pericarditis.(ABSTRACT TRUNCATED AT 400 WORDS)

Mitral stenosis

Associated lesions With severe pulmonary hypertension, a pansystolic murmur produced by functional tricuspid regurgitation may be audible along the left sternal border. This murmur is usually louder during inspiration and diminishes during forced expiration (Carvallo’s sign). When the cardiac output is markedly reduced in MS, the typical auscultatory findings, including the diastolic rumbling murmur, may not be detectable (silent MS), but they may reappear as compensation is restored. The Graham Steell murmur of pulmonary regurgitation, a high-pitched, diastolic, decrescendo blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension. This murmur may be indistinguishable from the more common murmur produced by aortic regurgitation (AR), although it may increase in intensity with inspiration and is accompanied by a loud and often palpable P2. Echocardiography

[From cardiac auscultation to echo-Doppler. Limitations of both methods].

Physiological tricuspid and pulmonary regurgitations are very often found by Echo-Doppler. They are generally slight, inaudible and devoid of significance. Tricuspid insufficiency nevertheless has the great advantage of enabling the calculation of pulmonary pressures. Auscultation is a good method for the diagnosis of rheumatic mitral insufficiency or related to prolapse, but is not reliable in other situations. Doppler is an excellent method for the qualitative and etiological diagnosis of mitral insufficiency but enables only semi-quantification. It also has the disadvantage of discovering minimal mitral insufficiency, the significance of which is uncertain. In contrast to auscultation, Doppler enables precise quantification in mitral stenosis. Auscultation is a good method for the diagnosis of aortic valve disease with the exception of slight insufficiency and stenosis in the elderly. Doppler enables the quantification of stenosis and semi-quantification of insufficiency. The existence of physiological aortic regurgitation is by no means certain. In conclusion, auscultation remains an important tool in cardiological diagnosis but has notable limitations. Echo-Doppler is a major advance but it is important to be aware of its limitations.

Cardiovascular examination

For the best cardiac examination, it is important to have the patient both sit up and lay down at a 30-45˚ angle. Tapping with the fingertips (also known as percussion) can be used to estimate the size of the heart, though palpation is more accurate. From the left side of the chest, the doctor can tap the spaces between the ribs with the tips of their middle finger to listen for the dullness that will be present over the heart. Listening with a stethoscope (also known as auscultation) to all four areas of the heart: aortic, pulmonic, tricuspid and mitral. Any murmurs, rubs or gallops should be noted. Gallops are also known as a third (S3) or fourth (S4) heart sound. The absence of abnormalities (normal) may be recorded as "no m/r/g". The ACC and the AHA have called cardiac auscultation "the most widely used method of screening for valvular heart disease." Because of its importance to the cardiac examination, cardiac auscultation has been covered in-depth elsewhere.

Cardiac examination

Finally the sacrum and ankles are checked for pitting edema which is caused by right ventricular failure in isolation or as part of congestive cardiac failure. Auscultation One should comment on S1 and S2 – if the splitting is abnormal or louder than usual. S3 – the emphasis and timing of the syllables in the word Kentucky is similar to the pattern of sounds in a precordial S3. S4 – the emphasis and timing of the syllables in the word Tennessee is similar to the pattern of sounds in a precordial S4. If S4 S1 S2 S3 Also known as a gallop rhythm. diastolic murmurs (e.g. aortic regurgitation, mitral stenosis) systolic murmurs (e.g. aortic stenosis, mitral regurgitation) pericardial rub (suggestive of pericarditis) The base of the lungs should be auscultated for signs of pulmonary oedema due to a cardiac cause such as bilateral basal crepitations.

Ventricular septal defect with aortic valve insufficiency in a New Zealand White rabbit.

A heart murmur was detected in a 10 mo old, female New Zealand White rabbit. Auscultation revealed cardiac murmurs both at the left and right hemithorax. Phonocardiography confirmed the systolic-diastolic nature of the left-sided and the systolic character of the right-sided murmur. Electrocardiography showed normal sinus rhythm; tall R waves and large T waves in lead II; and deep S waves in leads II, III, and aVF. Thoracic radiography demonstrated generalized cardiomegaly with prominent pulmonary vasculature. Echocardiography revealed a perimembraneous ventricular septal defect with aortic insufficiency. Signs of biventricular volume overload, relative pulmonic stenosis, and pulmonary valve insufficiency were also seen as consequences of the defect. Necropsy demonstrated a ventricular septal defect just below the aortic valve, a dilated pulmonary trunk, dilated and hypertrophied ventricles, dilated atria, and rightward displacement of the aortic root. Cardiac histopathology showed ventricular cardiomyocyte degeneration (swelling and hypereosinophilia of the cytoplasm with a loss of cross striation, and nuclear hyperchromasia), cartilaginous metaplasia of the aorta, and subendocardial fibrosis of the right ventricular flow tract.

Valvular heart disease

On auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy. Mitral regurgitation Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema.

The maverick heart sound.

An asymptomatic 29-year-old woman presented for prenatal counselling. She had a history of a heart murmur since childhood and a previous echocardiogram suggesting 'enlargement of the heart'. Physical exam revealed normal jugular venous pressure and contour. Precordial palpation was unremarkable. Auscultation, however, was abnormal; findings on inspiration and expiration are presented in Figure 1, sound clip. Based on the phonocardiogram and online supplementary audio clip, which of the following is correct? An early diastolic filling sound (S3) is heard, indicating increased right ventricular filling pressures.An ejection click without respiratory variation and a systolic ejection murmur are heard, consistent with bicuspid aortic valve stenosis.An ejection click with respiratory variation and a systolic ejection murmur are heard, consistent with pulmonic valve stenosis.A holosystolic murmur with inspiratory augmentation is heard, indicating tricuspid regurgitation.

Heart murmur

Mitral regurgitation typically is a holosystolic (pansystolic) murmur heard best at the apex, and may radiate to the axilla or precordium. A systolic click may be heard if there is associated mitral valve prolapse. Valsalva maneuver in mitral regurgitation associated with mitral valve prolapse will decrease left ventricular preload and move the murmur onset closer to S1, and isometric handgrip, which increases left ventricular afterload, will increase murmur intensity. In acute severe mitral regurgitation, a holosystolic (pansystolic) murmur may not be heard. Pulmonary valve stenosis typically is a crescendo-decrescendo systolic murmur heard best at the left upper sternal border, associated with a systolic ejection click that increases with inspiration (due to increased venous return to the right side of the heart) and sometimes radiates to the left clavicle.

Valvular heart disease

Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present Mitral stenosis Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy

InternalMed_Harrison

Tricuspid regurgitation (TR) with normal pulmonary artery pressures, as may occur with infective endocarditis, may produce an early systolic murmur. The murmur is soft (grade 1 or 2), is best heard at the lower left sternal border, and may increase in intensity with inspiration (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the jugular venous pulse. TR in this setting is not associated with signs of right heart failure. Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval after , end before S (Fig. 51e-1C), and are usually crescendo-decrescendo in configuration. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area, Fig. 51e-2) and radiates into the carotids. Transmission of the mid-systolic murmur to the apex, where it becomes higher-pitched, is common (Gallavardin effect; see above).

Double Orifice Mitral Valve -- History and Physical

A double orifice mitral valve (DOMV) is usually an asymptomatic entity unless accompanied by mitral valve stenosis, regurgitation, or a concomitant congenital cardiac anomaly. In patients with an associated congenital heart defect, it is usual for that particular disorder to manifest on clinical examination as there are no signs specific to DOMV. In isolated DOMV, the extent of symptoms depends on the grade of left atrial pressure resulting in pulmonary congestion. Symptoms are primarily due to diminished cardiac output and can range from tachypnea, dyspnea, and wheezing to poor feeding and failure to thrive in the pediatric population. In asymptomatic patients, the physical examination may be completely unremarkable as isolated DOMV is benign, even to cardiac auscultation. However, if complicated by mitral valve stenosis (MS), one may appreciate the murmur of MS, a low-pitched mid-diastolic murmur best heard at the apex. The same can be said for DOMV with mitral regurgitation (MR), a blowing pansystolic murmur is appreciated at the apical region. As patients develop symptoms, one may find clinical signs of heart failure such as increased work of breathing, peripheral cyanosis, increased jugular venous pressure, palpation of a parasternal heave, pulmonary crackles on auscultation as well as evidence of hypervolemia such as peripheral edema.

Right ventricular hypertrophy

People may rarely present with the symptoms of Ortner's syndrome, which include cough, haemoptysis and hoarseness. Signs On physical examination, the most prominent features are due to the development of right-sided heart failure. These can include a raised jugular venous pressure, ascites, left parasternal heave and a tender, enlarged liver on palpation. On inspection, patients may be chronically ill, cyanotic, cachectic and occasionally jaundiced. On auscultation, an accentuated second pulmonary sound (S2), a third heart sound termed a ‘right ventricular gallop’, as well as a systolic murmur over the tricuspid area accentuated by inspiration may be present. On occasion, the systolic murmur can be transmitted and auscultated over the liver. Less typically, diastolic murmur may also be heard as a result of pulmonary insufficiency.

InternalMed_Harrison

DIASTOLIC HeART MuRMuRS early Diastolic Murmurs (Fig. 51e-1E) Chronic AR results in a high-pitched, blowing, decrescendo, early to mid-diastolic murmur that begins after the aortic component of S2 (A2) and is best heard at the second right interspace (Fig. 51e-6). The murmur may be soft and difficult to hear unless auscultation is performed with the patient leaning forward at end expiration. This maneuver brings the aortic root closer to the anterior chest wall. Radiation of the murmur may provide a clue to the cause of the AR. With primary valve disease, such as that due to congenital bicuspid disease, prolapse, or endocarditis, the diastolic murmur tends to radiate along the left sternal border, where it is often louder than appreciated in the second right interspace. When AR is caused by aortic root disease, the diastolic murmur may radiate along the right sternal border. Diseases of the aortic root cause dilation or distortion of the aortic annulus and failure of leaflet

InternalMed_Harrison

imaging. The evidence base that links the findings from the history and physi-cal examination to the presence, severity, and prognosis of cardiovas-cular disease has been established most rigorously for coronary artery disease, heart failure, and valvular heart disease. For example, obser-vations regarding heart rate, blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes. Observations from the physical examination in this set-ting can inform clinical decision making before the results of cardiac biomarkers testing are known. The prognosis of patients with systolic heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the

Transthoracic echocardiogram

Structures Examples of TTE views of various structures of the heart. Aortic valve Mitral valve Tricuspid valve Pulmonary valve Measurements Routine TTE exams can provide a significant wealth of information about the heart's structure and function: Left ventricular size, thickness, systolic function, and diastolic function Right ventricular size and systolic function Aortic valve Aortic valve sclerosis & stenosis Aortic valve insufficiency Mitral valve Mitral stenosis Mitral regurgitation Tricuspid valve Tricuspid regurgitation (stenosis is possible, but rare) Pulmonary valve Pulmonary regurgitation (stenosis is possible, but rare) Inferior vena cava size as estimate of central venous pressure Aortic root size for thoracic ascending aortic aneurysm Pericardial effusion size

[Heart murmur--auscultation or echocardiography in the diagnostic assessment of congenital or valvular heart disease?].

The incidence of patients with degenerative valvular but also of patients with congenital heart disease surviving until adulthood or even old age will increase in the next decades. Auscultation with the stethoscope remains an important diagnostic means in the detection and treatment of heart disease. Heart murmurs (especially systolic heart murmurs) are extremely common. There are helpful clues to differentiate heart murmurs. It can occasionally be relatively simple to differentiate a systolic murmur due to valvular heart disease from an innocent, ejection murmur; however, there are important limitations of auscultation. Overall, auscultation and clinical examination alone do not suffice to correctly diagnose and treat patients with heart failure or a murmur Clinically significant aortic stenosis, aortic regurgitation and mitral regurgitation as well as hypertrophic cardiomyopathy are not uncommonly missed or misinterpreted. An echocardiographic exam is mandatory in all patients with more than a soft systolic murmur, any diastolic murmur, cardiac symptoms and/or ECG changes.

InternalMed_Harrison

The neck veins in patients with severe TR are distended with prominent c-v waves and rapid y descents (in the absence of TS). TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds. Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a positive hepatojugular reflex. A prominent RV pulsation along the left parasternal region and a blowing holosystolic murmur along the lower left sternal margin, which may be intensified during inspiration (Carvallo’s sign) and reduced during expiration or the strain phase of the Valsalva maneuver, are characteristic findings. The murmur of TR may sometimes be confused with that of MR unless attention is paid to its variation during the respiratory cycle and the extent of RV enlargement is appreciated. Atrial fibrillation (AF) is usually present in the chronic phase of the disease.

Valvular heart disease

Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries. Aortic regurgitation Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock.

Mitral stenosis

Diagnosis Physical examination Upon auscultation of an individual with mitral stenosis, the first heart sound is usually loud and may be palpable (tapping apex beat) because of increased force in closing the mitral valve. The first heart sound is made by the mitral and tricuspid heart valves closing. These are normally synchronous, and the sounds are termed M1 and T1, respectively. M1 becomes louder in mitral stenosis. It may be the most prominent sign. If pulmonary hypertension secondary to mitral stenosis is severe, the P2 (pulmonic) component of the second heart sound (S2) will become loud.

Aortic valve

Evaluation Evaluation of the aortic valve can be done with several modalities. Auscultation with a stethoscope is quick and easy. It contributes the A2 component to the second heart sound and changes with inspiration ("splitting") Transthoracic echocardiography (TTE) is used as the first test because it is non-invasive. Using TTE, the degree of stenosis and insufficiency can be quantified to grade the valve dysfunction. Transesophageal echocardiography is less often used for aortic stenosis & insufficiency because the angle between the probe and the aortic valve is not optimal (the best window is a transgastric view). MRI and CT can be used to evaluate the valve, but much less commonly than TTE. Quantification of the maximum velocity through the valve, the area of the opening of the valve, calcification, morphology (tricuspid, bicuspid, unicuspid), and size of the valve (annulus, sinuses, sinotubular junction) are common parameters when evaluating the aortic valve.

Jugular venous pressure

An exaggerated "y" wave or diastolic collapse of the neck veins from constrictive pericarditis is referred to as Friedreich's sign. Raised JVP, normal waveform Bradycardia Fluid overload Heart failure Raised JVP, absent pulsation Superior vena cava syndrome Large 'a' wave (increased atrial contraction pressure) Tricuspid stenosis Right heart failure Pulmonary hypertension Cannon 'a' wave (atria contracting against closed tricuspid valve) Atrial flutter Premature atrial rhythm (or tachycardia) Third degree heart block Ventricular ectopics Ventricular tachycardia Absent 'a' wave (no unifocal atrial depolarisation) Atrial fibrillation Large 'v' wave (c–v wave) Tricuspid regurgitation Absent 'x' descent Tricuspid regurgitation (sometimes 'x' wave is replaced by a positive wave) Prominent 'x' descent Cardiac tamponade Slow 'y' descent Tricuspid stenosis Cardiac tamponade Prominent & deep 'y' descent Constrictive pericarditis

Heart murmur

Tricuspid valve regurgitation presents as a holosystolic (pansystolic) murmur at the left lower sternal border with radiation to the left upper sternal border. Prominent v and c waves may be seen in the JVP (jugular venous pressure). The murmur will increase with inspiration. Hypertrophic obstructive cardiomyopathy (or hypertrophic subaortic stenosis) will be a systolic crescendo-decrescendo murmur best heard at the left lower sternal border. Valsalva maneuver will increase the intensity of the murmur, as will changing positions from squatting to standing. Atrial septal defect will present with a systolic crescendo-decrescendo murmur best heard at the left upper sternal border due to increased volume going through the pulmonary valve, and is associated with a fixed, split S2 and a right ventricular heave.

Heart murmur

Mitral stenosis typically presents as a diastolic low-pitched decrescendo murmur best heard at the cardiac apex in the left lateral decubitus position. It may be associated with an opening snap. Increasing severity will shorten the time between S2(A2) and the opening snap. (i.e. In severe MS the opening snap will occur earlier after A2) Tricuspid valve stenosis presents as a diastolic decrescendo murmur at the left lower sternal border, and signs of right heart failure may be seen on exam. Pulmonary valve regurgitation presents as a diastolic decrescendo murmur at the left lower sternal border. A palpable S2 in the second left intercostal space correlates with pulmonary hypertension due to mitral stenosis. Continuous and Combined Systolic/Diastolic Patent ductus arteriosus may present as a continuous murmur radiating to the back.

Valvular heart disease

Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valve's ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebstein's anomaly. Signs and symptoms Aortic stenosis Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional.

InternalMed_Harrison

Signs Many of the signs encountered in cor pulmonale are also present in HF patients with a depressed EF, including tachypnea, elevated jugular venous pressures, hepatomegaly, and lower-extremity edema. Patients may have prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation. Other cardiovascular signs include an RV heave palpable along the left sternal border or in the epigastrium. The increase in intensity of the holosystolic murmur of tricuspid regurgitation with inspiration (“Carvallo’s sign”) may be lost eventually as RV failure worsens. Cyanosis is a late finding in cor pulmonale and is secondary to a low cardiac output with systemic vasoconstriction and ventilation-perfusion mismatches in the lung.

Heart click

With newer, non-invasive imaging techniques, the origin of other, so-called adventitial sounds or heart clicks has been appreciated. These are short, high-pitched sounds. The mitral valve in cases of mitral stenosis may open with an opening snap on the beginning of diastole. Patients with mitral valve prolapse may have a mid-systolic click along with a murmur, referred to as apical late systolic murmur. Early systolic clicks may also be present in some patients. Aortic and pulmonary stenosis may cause an ejection click immediately after S1. References Symptoms and signs: Cardiac Audible medical signs

Pulmonary Regurgitation -- History and Physical

Cardiac examination findings are typically within normal limits in individuals with physiological pulmonary regurgitation. Some individuals with a lean physique may detect a faint early diastolic murmur in cases of mild pulmonary regurgitation. As pulmonary regurgitation increases significance, a systolic ejection murmur may be audible at the left upper sternal border due to increased right ventricle stroke volume. A third heart sound may be present, while a fourth one is uncommon. Mildly accentuated right ventricle impulse is generally observed in patients with severe pulmonary regurgitation; however, the jugular venous pressure is usually normal. A prominent jugular venous "a" wave may indicate pulmonary artery hypertension, while a prominent "v" wave is in patients with severe tricuspid valve regurgitation. [27]

Cardiogenic Pulmonary Edema -- History and Physical -- Physical Examination

Cardiovascular Findings Tachycardia and hypotension may be present along with jugular venous distention. Auscultation of the heart helps to differentiate between the various causes of valvular lesions causing pulmonary edema. Auscultation typically reveals an S3 gallop in volume overload states, which may be associated with accentuation of the pulmonic component of S2. Several different types of murmurs can be heard depending on the cause of the valvular lesion. Mitral stenosis produces a low-pitched, rumbling diastolic murmur associated with an opening snap at the apex, which becomes accentuated on expiration and produces loud S1. Mitral regurgitation produces a blowing, high-pitched pan-systolic murmur best heard at the apex, radiating to the left axilla and accentuating on expiration, producing soft S1. Aortic stenosis produces a harsh crescendo-decrescendo ejection systolic murmur at the aortic area, increasing on expiration, usually radiating towards the right side of the neck. Aortic regurgitation produces a high-pitched blowing early diastolic murmur best heard in the aortic area, greatest during expiration.


This is a patient with rheumatoid arthritis. In my opinion, as in these six months she has shown a clear clinical and biological improvement (decrease in acute phase reactants), I would maintain the therapeutic approach taken and wait for a new evaluation. However, I consider that this question could have another valid answer, 3. It depends a little on the attitude of each rheumatologist. If what you are looking for is a remission of the disease as soon as possible, you could choose to consider associating an anti-TNF alpha?

This is a patient with rheumatoid arthritis. In my opinion, as in these six months she has shown a clear clinical and biological improvement (decrease in acute phase reactants), I would maintain the therapeutic approach taken and wait for a new evaluation. However, I consider that this question could have another valid answer, [HIDDEN]. It depends a little on the attitude of each rheumatologist. If what you are looking for is a remission of the disease as soon as possible, you could choose to consider associating an anti-TNF alpha?

A 42-year-old female patient reports pain with inflammatory features and swelling in both wrists, 2nd and 3rd metacarpophalangeal and proximal interphalangeal joints bilaterally and left ankle of 4 months of evolution accompanied by morning stiffness of more than one hour duration. Hand X-ray shows an erosion in the styloid process of the ulna in the right carpus. Laboratory tests showed Hb: 10 g/dL with ESR of 45 mm in the first hour, CRP 16 mg/L, rheumatoid factor 160 IU/ML. After 6 months of treatment with indomethacin and methotrexate, the patient persists with pain and swelling of both carpals, morning stiffness lasting 30 minutes and a CBC showing an ESR 30 mm in the first hour and a CRP 9 mg/dL. Regarding the attitude to take, which of the following is true:

Suspend the prescribed treatment due to lack of response and initiate prednisone at high doses for symptom control only.

Maintain the therapeutic attitude taken since we have only been on it for 6 months and it would be necessary to wait a minimum of 9 months to evaluate therapeutic response.

If there is no medical contraindication, consider adding an anti-TNF alpha to the treatment.

Start a second disease-modifying drug as soon as possible, since it would not be possible to start treatment with biologic therapy alone after methotrexate.

Consider starting treatment with anti-CD20 therapy associated with methotrexate.

A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up.

To describe the frequency and duration of remission in the Utrecht rheumatoid arthritis cohort of patients followed since diagnosis, and the clinical and treatment characteristics of patients with remission v those without. In 1990 the Utrecht rheumatoid arthritis cohort study group started a clinical trial in which patients with recent onset of rheumatoid arthritis (<1 year) were randomised into four treatment groups: hydroxychloroquine (n = 169); intramuscular gold (n = 163); methotrexate (n = 166); and pyramid (n = 64). After two years, rheumatologists were allowed to prescribe any disease modifying antirheumatic drug. Remission was defined as: duration of morning stiffness < or =15 min, mean VAS pain < or =10 mm, Thompson joint score < or =10, and ESR < or =30 mm/h during at least six months. Cox regression analysis was used to determine baseline clinical, demographic, and treatment predictors of remission. Mean follow up duration was 62 months. Thirty six per cent achieved at least one period of remission. Median duration between diagnosis and the first remission period was 15 months for the intramuscular gold group, 18 months for the methotrexate and hydroxychloroquine groups, and 24 months for the pyramid group (NS). Predictors of remission were early response to initial treatment, less pain, rheumatoid factor negativity, and lower joint score at baseline. After a mean follow up duration of 62 months, only 36% of the patients had fulfilled the remission criteria at least once. A good response to treatment during the first year seems to be independently associated with remission rather than initial treatment alone.

[Leflunomide as a second choice treatment in patients with rheumatoid arthritis].

Leflunomide is a relatively new disease modifying antirheumatic drug (DMARD) and a number of studies evaluating its effectiveness and safety in daily medical practice is limited. Evaluation of effectiveness and safety of leflunomide treatment in patients with active rheumatoid arthritis in whom methotrexate was ineffective or contraindicated. Eighty one patients (66 women and 15 men) with RA diagnosed according to ARA (The American Rheumatism Association) criteria were included in the study. The mean age was 57.6+/-11.7 years and the mean disease duration was 7.7+/-7.1 years. The inclusion criteria were: disease activity according to DAS28 (Disease Activity Score)>3.2 and contraindications to methotrexate or ineffective methotrexate treatment for at least 3 months. At the beginning of the study 49 of patients were treated with methotrexate in weekly dose of 17+4.2mg and 32 were not treated with DMARDs. Oral glicocorticosteroids in stable doses of 5-15mg of prednisone were given to 66 (77.7%) of them. There was no statistically significant difference in radiological progression of the disease according to Steinbrocker's scale between groups (treated and not treated with methotrexate). Monotherapy with leflunomide was started with loading dose of 100mg for 3 days, and then 20mg daily. Combination therapy was introduced without loading dose. Evaluation was performed monthly and included: duration of morning stiffness, pain and disease activity according to VAS (visual-analogue) scale, the number of tender and swollen joints, blood count, ESR, CRP, aminotransferases activity, and the presence and intensity of adverse reactions. The results of treatment were evaluated after 5 months in 37 of patients and adverse reactions which happened until the end of 5th month were evaluated in all included patients. The mean DAS28 values improved exponentially during consecutive months and the difference between them was statistically significant. Adverse reactions during 5 months of treatment were observed in 36(44,4%) of patients and in 6(7,4%) of cases the treatment had to be stopped because of side effects. The frequency of adverse reactions was similar in monotherapy and combination therapy group. Leflunomide therapy can be effective in patients with active rheumatoid arthritis in whom methotrexate is contraindicated or insufficient. Combination of leflunomide with methotrexate is safe and does not increase the frequency of adverse reactions.

[Evaluation of methotrexate effect on the acute-phase response in rheumatoid arthritis after 12-week treatment].

DAS28 index calculated with regard for ESR, the number of swollen/painful joints and evaluation of the patient's condition by VAS is universally used to estimate activity of rheumatoid arthritis (RA). There is a variant of calculation using C-reactive protein (CRP) instead of ESR. Our experience indicates that ESR decreases more slowly than CRP during treatment and better reflects dynamics of patients' condition. From the practical standpoint it is important to estimate activity of RA because therapeutic modalities are chosen based on the DAS28 value. To study the influence of pharmaceutical form of methotrexate on the acute-phase response in rheumatoid arthritis. The study included 32 patients (24 women, 8 men) aged 19-76 (mean 47.5 +/- 28.5) yr with active RA (DAS28 > 3.2) 4-30 months (11.5 +/- 7.4, median 8) in duration. Diagnosis was made using AXR criteria (1987), none of the patients previously received methotrexate injections. Inclusion criteria: initially high ESR (Westegren, mm/hr) and/or CRP (mg/l measured by a highly sensitive method). All patients were given methotrexate subcutaneously for 12 weeks as monotherapy (initial dose 10 mg, maximum one 25 mg/week). The cumulative dose was 211.36 +/- 17.2 mg. Side effects did not require withdrawal of methotrexate. CRP level decreased faster than ERS: a 70% decrease of CRP by week 12 was recorded more frequently than that of ESR. Slow dynamics of the number of swollen joints compared with CRP may be due to the low cumulative dose of methotrexate. Duration of the disease had no effect on dynamics of acute phase characteristics. Methotrexate injections resulted in markedly delayed development of clinical signs of improvement compared with laboratory values. CFP levels fell down much faster than ESR, Remission or low activity of RA (estimated from DAS28) occurred only in 38% of the cases after 3 month monotherapy by methotrexate injections. It is concluded that efficacy of this drug should be estimated no sooner than 4 months after the onset of the treatment.

Pulse methotrexate therapy in rheumatoid arthritis. A controlled prospective roentgenographic study.

To assess whether weekly pulse methotrexate therapy alters radiographic progression of joint disease in patients with rheumatoid arthritis. Prospective, controlled study. Hand, wrist and foot roentgenograms obtained before, at the onset of, and during methotrexate treatment were scored for degree of joint-space narrowing and erosions by three rheumatologists using a standard method. Sequential sample of 24 patients with active definite or classical rheumatoid arthritis and previous unsuccessful treatment; of these, 3 were excluded due to drug ineffectiveness; 2, due to side effects; and 1, due to refusal to take methotrexate. Treatment with nonsteroidal anti-inflammatory drugs and prednisone was continued. Methotrexate was given weekly to control clinical evidence of disease in patients. After having had an average of 30 months of therapy, the 18 patients who continued to receive methotrexate therapy showed significant (p less than 0.05) clinical improvement, as evidenced by their decreased joint counts and joint scores, duration of morning stiffness, pain scales, and sedimentation rates. Despite patients' prolonged clinical improvement, the mean rate of development of erosions and joint-space narrowing during methotrexate therapy was not significantly different from the rate of radiographic progression before methotrexate therapy (0.043 compared with 0.041; p greater than 0.05). Weekly pulse methotrexate is effective for the long-term management of clinical disease activity in patients with refractory rheumatoid arthritis but may not be a disease-modifying agent by roentgenographic criteria.

Digital vasculitis in a patient with rheumatoid arthritis responded well to adalimumab.

42-year-old old female patient, followed up with diagnosis of rheumatoid arthritis for 15 years, was admitted with necrotising ulcer of left hand 1st and 2nd fingertips and pain, swelling, limitation of movement, and morning stiffness at bilateral wrist, and metacarpophalangeal and proximal interphalangeal joints. Laboratory tests revealed elevated acute phase reactants. Radial and ulnar arteries were clear in upper extremity Doppler ultrasound. The patient was diagnosed as RA activation and digital ulcer and administered iloprost infusion for five days and 1 mg/kg corticosteroid and 20 mg/week methotrexate (MTX). After one month, a partial regression of clinical and laboratory findings was observed. However, 6 months later, due to relapsed and increased complaints and findings, adalimumab 40 mg was administered. Two months later, clinical and laboratory findings apparently decreased.

Polymyalgia rheumatica

Another test that checks the level of C-reactive protein (CRP) in the blood may also be conducted. CRP is produced by the liver in response to an injury or infection, and people with polymyalgia rheumatica usually have high levels. However, like the ESR, this test is also not very specific. Polymyalgia rheumatica is sometimes associated with temporal arteritis, a condition requiring more aggressive therapy. To test for this additional disorder, a biopsy sample may be taken from the temporal artery. Treatment Prednisone is the drug of choice for PMR, and treatment duration is frequently greater than one year. If the patient does not experience dramatic improvement after three days of 10–20 mg oral prednisone per day, the diagnosis should be reconsidered. Sometimes relief of symptoms occurs in only several hours.

Remission in early rheumatoid arthritis treated with conventional DMARDs. Results of a two-year follow-up study of El Ayachi Moroccan cohort.

This study aimed to evaluate remission in patients with early RA treated by conventional DMARDs and to identify its possible predictor factors. Patients with early RA (<12 months) were enrolled in a 2-year follow-up study. Standard evaluation completed at baseline and at 24 months included clinical, laboratory, functional and structural assessment. Clinical remission after 2 years of follow-up was defined when DAS28 was less than 2.6. Possible predictor factors for remission were analyzed. Fifty-one patients (88.2% women, mean age of 46.9 [24-72] years, mean disease duration of 24 [6-48] weeks) were enrolled in this study. The delay in referral for specialist care was 140 [7-420] days. Rheumatoid factor, anti-CCP, HLA-DRB1*01 and DRB1*04 alleles were present respectively in 62.5, 56.6, 11.8, and 45.1% of patients. At 24 months, 77.2% received a median dose of 5 (0-8) mg/day of prednisone and 65.2% was taking methotrexate (MTX). 13.6% of patients had stopped their DMARD because of socioeconomic difficulties. At 24 months, we noted a significant improvement of morning stiffness, pain score, swollen joint count, ESR, CRP, DAS28 and HAQ scores. Remission at 2 years was noted in 34.8% of patients and was significantly associated in univariate but not in multivariate analysis to male sex (P=0.02) and to short delay in referral for specialist (P=0.03). In this cohort of early RA patients treated with conventional DMARDs, especially with methotrexate in monotherapy, remission at 2-year of follow-up was obtained in one third of patients. No predictor factors of remission were found out. These results should be verified by further studies.

Methotrexate

Not everyone with rheumatoid arthritis responds favorably to treatment with methotrexate, but multiple studies and reviews showed that the majority of people receiving methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis can be improved with combination therapy of tumor necrosis factor (TNF) or non-TNF biologics with methotrexate alone.

InternalMed_Harrison

In 2012 a joint task force of the ACR and EULAR updated the treatment guidelines for RA. They do make a distinction between patients with early RA (<6 months of disease duration) and patients with established RA. These guidelines highlight the need to switch or add DMARD therapy after 3 months of worsening or persistent moderate/high disease activity. If disease still persists after 3 months of intense DMARD therapy, addition of a biologic agent is warranted. Treatment with a biologic agent or aggressive combination DMARD therapy was also recommended as initial therapy in certain patients with high disease activity and poor prognosis. However, it has not been clearly established that this more intensive initial approach is superior to starting with methotrexate alone and, in the absence of an inadequate therapeutic response, moving rapidly to combination therapy.

Rheumatology

Treatment Most rheumatic diseases are treated with analgesics, NSAIDs (nonsteroidal anti-inflammatory drug), steroids (in serious cases), DMARDs (disease-modifying antirheumatic drugs), monoclonal antibodies, such as infliximab and adalimumab, the TNF inhibitor etanercept, and methotrexate for moderate to severe rheumatoid arthritis. The biologic agent rituximab (anti-B cell therapy) is now licensed for use in refractory rheumatoid arthritis. Physiotherapy is vital in the treatment of many rheumatological disorders. Occupational therapy can help patients find alternative ways for common movements that would otherwise be restricted by their disease. Patients with rheumatoid arthritis often need a long term, coordinated and a multidisciplinary team approach towards management of individual patients. Treatment is often tailored according to the individual needs of each patient which is also dependent on the response and the tolerability of medications.

Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab.

The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26-83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of <10 µg/mL were considered low and >10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of <10 µg/mL and the 42 with TCZ levels of >10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of >10 µg/mL and ESR, CRP levels, and DAS28.

Long-term efficacy and toxicity of cyclosporin A + fluocortolone + methotrexate in the treatment of rheumatoid arthritis.

The therapeutic efficacy and tolerability of the combination of cyclosporin A, methotrexate and fluocortolone was evaluated after 96 months of treatment in 140 patients with rheumatoid arthritis. The initial dose of CyA was 5 mg/kg per day and was subsequently modified on the basis of the individual clinical response. Fluocortolone was initially administered at a dose that was sufficient to control disease activity (80-130 mg/week) and then was gradually tapered down to a maintenance dose of 15-20 mg/week. MTX was given intravenously at a dose of 15 mg once weekly for 4 consecutive weeks and then, after a 2-week interval, every 2 weeks or every month depending on the evolution of the disease. At the end of the study a statistically significant improvement was observed in both clinical (VAS, grip-strength, duration of morning stiffness, number of swollen joints, number of painful joints, Ritchie's index and Lee's functional index) and laboratory parameters: ESR (p = 0.000); alpha 2 globulins (p = 0.000); hemoglobin (p = 0.000); CRP (p < 0.001); and rheumatoid factor (p = 0.000). Radiological evaluation revealed little progression in anatomic lesions (Larsen score p = 0.699; number of erosions p = 0.344), thus suggesting that our protocol may be capable of showing down both bone resorption and cartilage loss. Renal toxicity, defined as an increase in plasma creatinine concentrations of more than 50% of the baseline value, was observed in 12 patients (8.5%), but the drug was discontinued in only one, who simultaneously presented high blood pressure. The positive results so far achieved in our study must be interpreted as being due to the combined action of the individual drugs, which made it possible for them to be used at relatively low dosages that minimised the onset of their side effects while maintaining the efficacy of their suppressive action.

Five-year followup of rheumatoid arthritis patients after early treatment with disease-modifying antirheumatic drugs versus treatment according to the pyramid approach in the first year.

To evaluate whether the clinical advantages observed after 1 year in a randomized controlled clinical trial, in which 2 treatment strategies were compared (the early disease-modifying antirheumatic drug [DMARD] approach versus the pyramid approach), persist after 5 years. In this study, 238 patients with recently diagnosed rheumatoid arthritis (RA) were randomized to either the pyramid group (n = 56) or the early DMARD group (n = 182). Patients assigned to the pyramid group received nonsteroidal antiinflammatory drugs for at least 1 year after inclusion (the mean +/- SD lag time until first prescription of a DMARD was 14 +/- 9 months). Patients in the early DMARD group were treated with a DMARD immediately after inclusion. After 5 years, data were available for 44 patients in the pyramid group (79%) and 145 patients in the early DMARD group (80%). No prolongation of the clinical advantages in favor of the early DMARD group, as observed after the first year, was demonstrated. Nevertheless, a significantly shorter delay time until complete response and a higher number of patients with overall clinically relevant improvement at several assessment points were observed in the early DMARD group compared with the pyramid group. The clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year.

Prognosis of 5-year radiographic erosions of the wrist according to early, late, and persistent wrist swelling or tenderness in patients with early rheumatoid arthritis.

To determine whether early inflammatory activity in the first year of disease compared to persistent or later occurrence of swelling or tenderness in the wrist joints is associated with 5-year erosions in the same joint in patients with early rheumatoid arthritis (RA). A cohort of 195 patients with early active RA was enrolled in the Finnish RA Combination Trial. Swelling and tenderness of wrists were assessed at baseline and at 3, 6, 12, 24, 36, and 48 months. Radiographs of the wrists were taken at the baseline and at 5 years. The 237 wrist joints of 125 patients without erosions at baseline were classified according to wrist swelling, i.e., I: never swollen; II: swollen during first year only; III: swollen during the second to fourth year only; and IV: swollen during the first year and followup, and similarly according to tenderness. Thirty percent of the wrists were never swollen in all clinical examinations; 43% were swollen only during the first year; 11% were not swollen in the first year, but were swollen at some time during 24-48 months; and 16% of wrists were swollen during the first year and at some time during 24-48 months. At 5 years, 64% of 237 wrists remained free of erosions. Erosions developed in 82% of wrists that were swollen during both the first year and 24-48 months, versus 56% of wrists that were not swollen at first year but were swollen during 24-48 months, 31% of wrists that were swollen during the first year only, and 11% of wrists that were never swollen. Similar results were seen for joint tenderness. Wrist swelling during the first year only is associated with less future wrist radiographic damage than persistent swelling or swelling only during the followup. Our results emphasize the value of early and continuous suppression of inflammatory activity in early RA.

Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: a one-year prospective study.

To compare the effectiveness and toxicity of cyclosporin A (CsA) vs low-dose methotrexate (MTX) over a period of one year in the treatment of psoriatic arthritis (PsA) with peripheral involvement. Thirty-five patients with PsA were enrolled in a prospective, controlled, randomized trial. CsA was initially given in doses of 3 mg/kg/day to a maximum permitted dose of 5 mg/kg/day; MTX was given in oral doses of 2.5 mg every 12 hours for 3 consecutive doses each week up to a maximum dose of 15 mg/weekly. Clinical and laboratory evaluations were performed at entry and monthly thereafter. After 6 and 12 months the number of painful joints, the number of swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, CRP, the patient's and the physician's assessment of PsA activity, as well as the PASI, were significantly improved in both treatment groups. ESR values were significantly reduced only in the MTX group (p < 0.01), which also showed a significantly increase of liver enzymes. The changes in the main clinical and laboratory parameters during the course of CsA or MTX treatment were not significantly different except for the AST and ALT levels (p < 0.05). After one year of therapy CsA and MTX were withdrawn in 41.2% and 27.8% of the patients respectively, but these differences were not statistically significant. Our one-year prospective trial shows that low-dose CsA and MTX are both effective in the treatment of PsA, but the differences in the tolerability of these drugs must be considered at the start of therapy.

The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.

To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. Open, randomized clinical trial. Outpatient clinics of six clinical centers. 238 consecutive patients with recently diagnosed rheumatoid arthritis. Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.

[Early arthritis: action desired - treatment required].

Rheumatoid Arthritis (RA) is the most prevalent inflammatory joint disease in adults and shows a destructive course in most cases. The outcome of the disease - functional decline and invalidity - necessitates an early therapy. Recent studies demonstrate that the initiation of the treatment with a disease modifying antirheumatic drug (DMARD) treatment within the first three months after the onset of symptoms is crucial for sustained improvement of prognosis as well as therapeutic success and outcome. In the early stage of the disease, the criteria for the classification of Rheumatoid Arthritis (RA) are frequently not met. Up to over 50% of the patients show an arthritis, which cannot be classified and therefore is seen as undifferentiated arthritis (UA). Early therapeutic intervention appears to prevent the chronification of the disease; thus an early and appropriate disease modifying therapy is mandatory. Age, gender, involvement of the hands, positive rheumatoid factor, as well as the detection of anti cyclic-citrullinated peptide antibodies (anti-CCP Ab) are predictors of the development of RA. Beside conventional X-rays, there are other imaging methods such as magnetic resonance tomography imaging, Power-Doppler or contrast medium enhanced sonography, which may enable the detection not only of synovitis but also of erosive lesions at very early stages. Those patients suffering from UA carry a high risk for the development of a destructive arthritis as seen in RA, and therefore should be treated with an adequate DMARD. In these cases methotrexate is still the drug of first choice.

[Case of successful pregnancy and childbirth in a rheumatoid arthritis patient treated with etanercept].

The patient was a 34-year-old woman who, at age 23, was diagnosed with rheumatoid arthritis (RA) presenting with morning stiffness, swelling and tenderness of bilateral knee joints and metacarpophalangeal (MP) joints of the right second and third fingers, increased C-reactive protein (CRP) levels, and a high level of rheumatoid factor (RF). The patient was maintaining remission with oral dose of bucillamine (BUC; 300 mg/day); however, due to the deterioration of arthralgia at age 26, she was additionally administered 8 mg/week of methotrexate (MTX), which improved the symptoms. Thereafter, the prescription of BUC was discontinued. At age 31, she experienced onsets of swelling and tenderness in both the knee joints and wrists and in MP joints of the right second and third fingers; further, CRP levels increased to 5.44 mg/dL, resulting in increased RA activity. The concomitant administration of infliximab was started at a dose of 3 mg/kg, which helped achieve favorable RA control. At age 32, approximately 2 years before childbirth, the prescription of infliximab was changed to 25 mg/dose of etanercept administered twice a week because the patient wished to conceive. Remission was maintained even after the drug change; therefore, MTX was discontinued and the patient was treated with etanercept alone. After she was confirmed to be pregnant in March of the following year, administration of etanercept was continued for treating of RA even during pregnancy. During that time, RA was favorably controlled, and the patient gave birth to a baby boy weighing 3192 g in October of the same year. The Apgar score of the baby was favorable. This case is considered important because, to the best of our knowledge, this may be the first report of a planned pregnancy and childbirth in a patient under administration of a biological preparation.

Sixth-month remission as a predictor for twelve-month remission in polymyalgia rheumatica.

To investigate clinical and laboratory prognostic factors of remission after one year of follow-up in patients with polymyalgia rheumatica (PMR) treated with low-dose prednisone. In this observational study, in a monocentric Italian Rheumatology Unit, we enrolled eighty-one consecutive PMR patients. Clinical and laboratory tests were performed every 3 months. Clinical remission was defined as the lack of symptoms, while laboratory remission was defined as erythrocyte sedimentation rate ≤40 mm/h and C-reactive protein (CRP) ≤0.5 mg/dl. Thirty-eight patients reached complete (clinical and laboratory) remission after 12 months of follow-up. A significant lower percentage of complete remission was seen in female gender compared to male (33.9 % vs. 78.2%, p=0.0001) at univariate analysis. No significant differences were found at baseline according to response to therapy during follow-up, while CRP values at the sixth month were significantly lower in patients who reached complete remission after one year (median: 0.4 mg/dl vs. 1 mg/dl, p=0.017). CRP<0.5 mg/dl at 6 months was independently associated with complete remission at 12 months in the multivariate analysis. The sixth month of therapy is a target for the management of PMR because it can help to identify patients at greater risk of exacerbations, who may benefit from a tighter follow-up and more aggressive therapeutic strategy. Higher CRP values at 6 months appear to be associated with a higher risk of longer steroid therapy.

Can Cyclosporine-A associated to methotrexate maintain remission induced by anti-TNF agents in rheumatoid arthritis patients? (Cynar pilot study).

Biological therapies, such as etanercept, adalimumab and infliximab, have demonstrated good efficacy in inducing rheumatoid arthritis to low disease activity levels. Nevertheless, their cost, as well as the related risk of side effects, especially in long-term therapies, are still high. Furthermore, there is a good deal of evidence proving loss of efficacy of such therapies in the long term, often necessitating the shift from one specific anti-TNF biological treatment to another. There are also other open debates on the amount of time a patient should undergo an anti-TNF therapy, on the possibility of inducing a complete remission in early arthritis and, once remission or low disease activity is obtained, on the possibility of interrupting the anti-TNF-based therapy. In this study we investigated whether A-Cyclosporin and Methotrexate association may be effective in maintaining low disease activity obtained by anti-TNF therapies. Twenty-three rheumatoid arthritis-affected patients, whose diagnosis was made according to ACR criteria, with a disease duration of less than 3 years, and DAS28<3.2 that reached a level of low disease activity within 6-8 months from beginning anti-TNF and Methotrexate therapy, were enrolled in the study. After the suspension of anti-TNF therapy, patients were started on A-Cyclosporine (2-3 mg/kg/day) and Methotrexate (15mg/week) therapy. DAS28, Pain VAS, Erythrosedimentation Rate (ESR), and C Reactive Protein (CRP) were all tested at time 0 and at 6 months, as well as liver and kidney profiles, after the interruption of the anti-TNF therapy and the beginning of A-Cyclosporine and Methotrexate therapy. Side effects were also recorded. Of 23 patients undergoing the A-Cyclosporin and Methotrexate therapy for maintaining low disease activity in rheumatoid arthritis obtained by 6-8 months of anti-TNF therapy, 21 completed the study with a 6 month follow-up. Thirteen patients maintained clinical parameters within low disease activity values, while 8 patients showed an increase in DAS28 and other parameters. Only two patients showed an increase in blood pressure that was diagnosed after two months from the beginning of the A-Cyclosporin and Methotrexate therapy. The reduction in the dosage of A-Cyclosporin from 3mg/kg/day to 2mg/kg/day caused a slow normalization of blood pressure values. Our data seem to suggest that more than half of the patients undergoing A-Cyclosporin and Methotrexate therapy seemed to maintain low disease activity parameters of rheumatoid arthritis, obtained after 6-8 months of anti-TNF therapy. Further studies on larger populations are necessary in order to confirm such results and identify predictor factors for different responses.

The anti-rheumatic effect of multiple synovectomy in patients with refractory rheumatoid arthritis.

We assessed the anti-rheumatic effects of radical multiple synovectomy (RaMS) in patients with rheumatoid arthritis (RA) who did not respond to intensive medical treatment. The selection of patients into three groups, A, B or C, was randomised. Patients assigned to group A (n = 28) continued the prescribed pre-operative medication and had RaMS. Patients assigned to group B (n = 20) were started on a combination therapy with disease-modifying anti-rheumatic drugs (DMARDs) after radical multiple synovectomy. Nineteen RA patients who were started on the same combination therapy as group B but who did not undergo surgery served as controls (group C). The clinical and radiographic findings were assessed for at least 3 years after surgery. Patients in the surgically treated groups (groups A and B) showed a significant reduction in the number of swollen and painful joints and in their ESR and serum CRP levels, and this effect was maintained for at least 3 years. More than 40% of the patients remained in clinical remission during the observation period. The surgical outcome seemed to be superior to that of the controls and did not differ between group A and group B. Articular destruction (assessed by the carpal height ratio) did not progress in the patients who were in clinical remission.

A randomized double-blind controlled trial of sulphasalazine combined with pulses of methylprednisolone or placebo in the treatment of rheumatoid arthritis.

Thirty-eight patients with rheumatoid arthritis meeting American College of Rheumatism (ACR) criteria were entered in a randomized controlled trial (RCT) of 6 months to assess whether monthly treatment with i.v. methylprednisolone (MP) enhances or accelerates the efficacy of sulphasalazine (SSZ). All patients had failed at least one second-line agent and were randomized to receive SSZ (2g/day) and pulses of MP (5 mg/kg), or SSZ+ (2 g/day) and pulses of saline (SA). A single infusion of 2 h was carried out in both groups for a total of three times (0, 1 and 2 months). The two groups were comparable at baseline regarding their demographic and clinical characteristics. Disease activity was evaluated every 2 months by means of: (1) joint count; (2) morning stiffness; (3) grip strength; (4) visual analogue pain score; (5) health assessment questionnaire; and (6) erythrocyte sedimentation rate. All outcome measures improved significantly in both groups (P < 0.001). Evaluation at each follow-up visit showed no significant differences between the groups in any of the adverse effects attributable to SSZ therapy (one SA vs two MP). Adverse effects attributable to SA/MP therapy were rare and mild. We concluded that repeated pulses of MP during the first 3 months of treatment did not improve the efficacy of SSZ. Therefore, there is no justification for using MP in this way during the induction phase of SSZ therapy.

Micafungin plus fluconazole in an infected knee with retained hardware due to Candida albicans.

To describe the use of micafungin and fluconazole in the management of a fungal prosthetic joint infection caused by Candida albicans. A 55-year-old female who had undergone total left knee arthroplasty due to rheumatoid arthritis presented with symptoms of a left knee infection. Intravenous vancomycin 1 g every 12 hours and intravenous ampicillin/sulbactam 1.5 g every 6 hours were initiated. Arthrocentesis produced cloudy synovial fluid with a white blood cell (WBC) count of 5.995 x 10(3)/microL. C-reactive protein (CRP) was 19.8 mg/dL and erythrocyte sediment rate (ESR) was greater than 120 mm/h. Gram stain was negative, but intraoperative cultures grew C. albicans. Four days later the patient's condition worsened and repeat arthrocentesis showed WBC count of 16.8 x 10(3)/microL with budding yeast in the synovial fluid. Antibiotics were stopped and liposomal amphotericin B 5 mg/kg once daily was started but was stopped after a few doses due to renal failure. Intravenous micafungin 100 mg daily was initiated; intravenous fluconazole 400 mg daily was added 2 days later and subsequently changed to oral fluconazole after 2 days of therapy. The patient received combination micafungin/fluconazole therapy for 8 weeks. After approximately 8 weeks of therapy, the CRP level and ESR had decreased from 19.8 to 7.1 mg/dL and greater than 120 to 81 mm/h, respectively. The patient's pain and range of motion in her knee had returned to baseline levels at last follow-up after the total knee arthroplasty. After 8 weeks of combination therapy, micafungin was discontinued but oral fluconazole was continued; approximately 8 weeks later the patient relapsed, requiring removal of the prosthetic knee hardware. Fungal prosthetic joint infections are rare, but definitive data regarding appropriate treatment are lacking. Echinocandins are an attractive treatment option due to their enhanced biofilm penetration. In our patient, treatment with micafungin plus fluconazole for 8 weeks followed by fluconazole monotherapy was associated with an initial good outcome in the treatment of a C. albicans prosthetic knee infection with retained hardware. This was, to our knowledge, the first case using micafungin in a prosthetic joint infection. Although micafungin plus fluconazole showed positive results in our patient, more data are needed regarding combination therapy for fungal prosthetic joint infections.

What is the best treatment strategy for early RA?

Treatment of early rheumatoid arthritis has to be started very early, when the diagnosis is made, preferentially before 6 months of symptoms. Combination therapy with conventional disease-modifying anti-rheumatic drugs (DMARDs) with low-dose, oral glucocorticoids in the induction phase from the start gives the best results. The patient should be monitored systematically, at start between 1 and 3 months, and the patient should have access to additional visits if a flare or arthritis or adverse event occurs. The treatment should aim to remission (no tender and swollen joints, no signs of inflammatory activity), which can be reached by 60-80% of the patients. Intra-articular glucocorticoid injections as part of the treatment strategy increase the suppression of arthritis and retard joint destruction. Biological drugs are reserved for patients who have consistent active disease and who do not respond to conventional combinations.

Autologous stem cell transplantation: a possible treatment for refractory juvenile chronic arthritis?

In adults, autologous stem cell transplantation (ASCT) has been described recently as a possible treatment for severe autoimmune disease refractory to conventional treatment. We report here the four first children with severe forms of juvenile chronic arthritis (JCA) treated with ASCT. We studied three children with systemic JCA and one child with polyarticular JCA. Unprimed bone marrow was harvested 1 month prior to ASCT. T-cell depletion of the graft was performed with CD2 and CD3 antibodies. We used a preparative regimen of antithymocyte globulin (ATG; 20 mg/kg), cyclophosphamide (Cy; 200 mg/kg) and low-dose total body irradiation (TBI; 4 Gy). Methotrexate (MTX) and cyclosporin A (CsA) were stopped before ASCT; prednisone was tapered after 2 months. After ASCT, our patients showed an anti-inflammatory-drug-free follow-up of 6-18 months with a marked decrease in joint swelling, pain and morning stiffness. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and haemoglobin (Hb) returned to near-normal values within 6 weeks. Despite T-cell depletion, there was a very rapid immune reconstitution. Two patients developed a limited varicella zoster virus (VZV) eruption which was treated by acyclovir.

InternalMed_Harrison

Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional DMARDs; and biologic DMARDs (Table 380-2). Although disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of

InternalMed_Harrison

As mentioned earlier, methotrexate is the DMARD of first choice for initial treatment of moderate to severe RA. Failure to achieve adequate improvement with methotrexate therapy calls for a change in DMARD therapy, usually transition to an effective combination regimen. Effective combinations include: methotrexate, sulfasalazine, and hydroxychloroquine (oral triple therapy); methotrexate and leflunomide; and methotrexate plus a biological. The combination of methotrexate and an anti-TNF agent, for example, has been shown in randomized, controlled trials to be superior to methotrexate alone not only for reducing signs and symptoms of disease, but also for retarding the progression of structural joint damage. Predicting which patients will ultimately show radiologic joint damage is imprecise at best, although some factors such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are associated with increased

[Effects of wenhua juanbi recipe on TNF-alpha and IL-1beta in peripheral blood of rheumatoid arthritis patients].

To observe the clinical effect of Wenhua Juanbi Recipe (WJR) in treating rheumatoid arthritis (RA), its effects in reducing the dosage of Western medicine used and stabilizing condition of disease, as well as its influences on peripheral blood levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and anti-cyclic citrullinated peptide antibody (anti-CCP), for the sake of exploring its preliminary acting mechanism. One hundred patients with RA were randomly assigned to 2 groups, the control group and the treated group, 50 in each group. All were treated with oral administration of methotrexate (MTX,7.5 mg per week), sulfasalazine (0.5 g, tid) and meloxicam (Mobic, 7.5 mg, bid), but to the treated group WJR was given additionally. The therapeutic course for both groups was 3 months. Clinical effect, changes of symptoms and physical signs, dosages of western medicines used, and laboratory indices in 2 groups after treatment were observed, and cases of relapse 3 months after treatment were figured out. The total effective rate in the treated group was higher than that in the control group (88.0% vs 76.0%, P<0.05). The improvements in scores of symptoms and signs [joint pain (0.61 +/- 0.59), swelling (1.49 +/- 1.20), tenderness (0.90 +/- 0.69), movement (0.68 +/- 0.62), griping strength (68.56 +/- 6.50) mm Hg, morning stiff time (23.26 +/- 9.26) min], and in levels of laboratory indices (TNF-alpha, IL-1beta, anti-CCP, RF, ESR, CRP, PLT and Ig) in the treated group after treatment were significantly superior to those in the control group (P<0.05 or P<0.01). The dosages of MTX [(82.11 +/- 11.35) mg vs (94.75 +/- 10.23) mg] and meloxicam [(108.85 +/- 16.13) mg vs (189.63 +/- 18.44) mg] used, and the relapse rate in the treated group were lower significantly (P<0.05, P<0.01) than those in the control group respectively. Effect of combined therapy of WJR and Western medicines is superior to that of using Western medicines alone in treating RA; WJR can reduce the dosages of Western medicines used and the relapse rate, as well as stabilize the condition of illness. It has the effects of immune regulating and anti-inflammatory reaction. Its mechanism for treating RA is possibly the inhibition on cytokines of TNF-alpha and IL-1beta.

The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis.

Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfillment of remission criteria at weeks 2, 12 or 52, time course of 'core set variables' and proportion of patients starting DMARDs. 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

Rheumatoid arthritis

Monitoring progression Many tools can be used to monitor remission in rheumatoid arthritis. DAS28: Disease Activity Score of 28 joints () is widely used as an indicator of RA disease activity and response to treatment. Joints included are (bilaterally): proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. The erythrocyte sedimentation rate (ESR) is measured and the affected person makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as: From this, the disease activity of the affected person can be classified as follows:

Toxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole.

A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure.

Patient retention and hand-wrist radiograph progression of rheumatoid arthritis during a 3-year prospective study that prohibited disease modifying antirheumatic drugs.

To quantitate patient retention and radiographic progression rates in serial hand/wrist radiographs of patients with rheumatoid arthritis (RA) who were not being treated with disease modifying antirheumatic drugs (DMARD). A total of 1433 RA patients with 1-7 years' disease duration entered a 3-year prospective randomized double-blind clinical trial comparing the nonsteroidal antiinflammatory drugs (NSAID) etodolac (300 or 1000 mg daily) and ibuprofen (2400 mg daily). Standardized hand/wrist radiographs were obtained yearly and at dropout if > 6 months after entry. DMARD were not permitted. Joint erosion, joint space narrowing (JSN), and total scores of 3 readers were averaged. At entry, mean duration of RA was 3.5 years (range 1-7); ages were 21-78 years; patients were 71% female, 84% Caucasian, 67% rheumatoid factor (RF) positive; tender joint count was 29, swollen joint count 22, Westergren erythrocyte sedimentation rate (ESR) 49, and C-reactive protein (CRP) 2.44. There were 824 (57.5%) patients who completed >or= 6 months and had paired radiographs; 46% completed 48 weeks; 31%, 98 weeks; and 19%, 147 weeks. Months between paired radiographs (time in study) averaged 23.1 (range 6-36). Mean progression rates for total, erosion, and JSN scores (5.08, 2.53, and 2.54 units per year, respectively) were significantly associated with time in study, baseline RF, ESR, CRP, swollen joint count, presence of erosions at entry, and with 20% and 50% composite clinical responses. Painful joint count and RA duration were weakly associated only with progression of erosions. Progression rates were not associated with age, sex, corticosteroid use, or prior DMARD use. Patients who completed the 3-year trial had less severe disease activity and radiographic progression than those who dropped out. In this 3-year prospective double-blind clinical trial that prohibited DMARD, retention rates (57.5%, 46%, 31%, and 19% at 0.5, 1, 2, and 3 years) were similar to those in the non-DMARD-treated placebo groups of recent published studies. Radiographic progression rates are reported for 824 non-DMARD-treated patients during RA of 1-10 years' duration. This information may be useful as background information in the interpretation of longterm clinical trials that evaluate joint radiographic outcomes.