Chest pain with pancytopenia and artrtis
A 27-year-old woman presents to the emergency room complaining of retrosternal chest pain for the past 2 days. The pain is constant, not associated with exertion, worsens when she takes a deep breath, and is relieved by sitting up and leaning forward. She denies any shortness of breath, nausea, or diaphoresis. On examination, her temperature is 37.4°C, heart rate 124 bpm, and blood pressure 118/72 mm Hg. She is sitting forward on the stretcher, with shallow respirations. Her conjunctivae are clear and her oral mucosa is pink, with two aphthous ulcers. Her neck veins are not distended; her chest is clear to auscultation and is mildly tender to palpation. Her heart rhythm is regular, with a harsh leathery sound over the apex heard during systole and diastole. Her abdominal examination is benign, and her extremities show warmth and swelling of the proximal interphalangeal (PIP) joints of both hands. There is an erythematous raised patch on her chest. Laboratory studies are significant for a white blood cell (WBC) count of 2100/mm3, hemoglobin concentration 10.4 g/dL with mean corpuscular volume (MCV) 94 fL, and platelet count 78,000/mm3. Her blood urea nitrogen (BUN) and creatinine levels are normal. Proteinuria is detected by urine dipstick. Quantitative protein excretion is 600 mg/day. A urine drug screen is negative. Chest x-ray is read as normal, with a normal cardiac silhouette and no pulmonary infiltrates or effusions. The electrocardiogram (ECG) is shown in the Figure
.
• What is the most
likely diagnosis?
*
*
*
*
*
*
Criteria for the classification of
Systemic Lupus Erythematosus
(SLE). A patient is classified as having SLE if any 4 or more of 11 criteria are met.
Pericarditis:
diffuse concave (saddle-shaped) ST segment elevation in association with
PR-segment depression.
STEMI
: planar, non-concave ST-segment elevation (> 0.1 mV = 1mm) in two or more
contiguous leads (ie, in the same vascular territory)
Differential Diagnosis STEMI ≠ Pericarditis
If a patient with acute pericarditis is treated with thrombolytics for infarction, pericardial hemorrhage and cardiac tamponade may develop .
Pulsus paradoxusis an abnormally large decrease in systolic blood pressure and pulse wave amplitude during inspiration.
A 45 year old lady of South Asian origin presents with sudden weakness of her left arm and right leg for 8 hours. There was no associated slurring of speech, difficulty in swallowing, or sensory disturbances. She was diagnosed with delusional disorder 3 months ago, after experiencing paranoid delusions for 1 year, and is currently on treatment with haloperidol. Her medical and surgical histories are unremarkable, and there is no family history of stroke, heart disease or thrombotic disorders. She is not on oral contraceptives, has never been pregnant, and does not smoke or consume alcohol. She denies using recreational drugs. Serial ECGs are found to be normal, while her random capillary blood glucose is 105 mg/dL. Her complete blood count is significant for aplatelet count of 68,000/mm3. ESR, CRP, serum electrolytes, and her liver and renal profiles are all normal.
Multiple bilateral strokes
Select Relevant Investigations
MRI Brain the MRI scan reveals multiple cortical infarcts involving both hemispheres.
Echocardiographythe echocardiogram shows an ejection fraction of 70% with no valvular abnormalities, intracardiac thrombi or akinetic segments.
Serum Homocysteineserum homocysteine levels are within the normal range.
Antiphospholipid Screen Lupus anticoagulant: moderately positive. Anticardiolipin antibody: moderately positive. ANA and dsDNA: negative
Select Relevant Management
• rTPA Not Performed
• Enoxaparin Not Performed
• Warfarin Performed
This 45 year old lady has developedacute flaccid paralysis of both her left upper limb, and right lower limb; there are no cerebellar signs, and sensation is unaffected, as are the cranial nerves. These clinical findings are most suggestive of a
stroke involving both cerebral hemispheres; this is confirmed by MRI imaging of the brain, which reveals bilateral cortical infarcts.
Note that relatively few etiologies can give rise to multiple bilateral strokes; predominantly among these are cardiac thromboembolism and thrombophilic states. However, her examination and an ECG reveal no evidence of cardiac rhythm abnormalities, while echocardiography shows no structural cardiac defects or intracardiac thrombi. In addition, while she is obese (note that the BMI ranges are different for South Asians), she is not diabetic or hypertensive, and has no other obvious cardiovascular risk factors.
A vast range of genetic and acquired thrombophilias exist; however, relatively few of these give rise to arterial thromboses. Key possibilities which need to be considered in this specific patient include vasculitic syndromes, hyperhomocysteinemia,antiphospholipid syndrome(APS), and paroxysmal nocturnal hemoglobinuria(PNH). Note that there are no clinical features suggestive of a vasculitis; nor are inflammatory marker levels elevated. In addition, while her history of psychotic symptoms and the finding of thrombocytopenia are suggestive of systemic lupus erythematosus (SLE), insufficient criteria are present to establish this diagnosis. The absence of anemia and hyperbilirubinemia argues against PNH, as does the lack of supportive signs and symptoms. Serum homocysteine levels are also normal, ruling out hyperhomocysteinemia.
However, the antiphospholipid antibody screen is positive, strongly suggesting that antiphospholipid syndrome is the diagnosis. Note that this should be repeated after 12 weeks; a repeat positive result is essential to confirm the presence of APS. She should be started onwarfarinas soon as possible, after a baseline coagulation profile has been obtained. Note that the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the management of acute stroke only recommend thrombolytic therapy in patients who present in the first 4.5 hours following the event. Furthermore, Enoxaparin, which is a low molecular weight heparin, is not recommended in the management of arterial thrombotic events; Corticosteroid therapy has not been proven to be effective in APS.
Paroxysmal nocturnal hemoglobinuria (PNH) (Strübing-Marchiafava-Micheli syndrome) originates from an acquired mutation in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A). The PIGA protein is involved in the first step in the synthesis of the glycosylphosphatidylinositol (GPI) anchor, a glycolipid that links dozens of cell-surface proteins to the plasma membrane on hematopoietic cells. Complement-mediated intravascular hemolysis is largely due to lack of the GPI-linked complement inhibitor CD59 on the surface of red blood cells. Anemia in PNH is largely due to intravascular hemolysis. The pathogenesis of thrombosis in PNH is multifactorial and incompletely understood. Free hemoglobin released from RBCs scavenges nitric oxide (NO), which in turn leads to vasoconstriction and possibly endothelial cell activation and expression of tissue factor.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder. Reported incidence of clinically significant disease is in the range of 1 to 10 cases per million population, although this may be an underestimate. Clinical findings include unexplained hemolytic anemia, thrombosis in an atypical location. Thrombosis is the leading cause of death in PNH. Laboratory findings in PNH include typical findings of hemolytic anemia, loss of glycosylphosphatidylinositol (GPI)-anchored proteins.
The typical evaluation involves initial testing to determine that the patient has a hemolytic anemia; and to eliminate autoimmune, microangiopathic, and mechanical causes of hemolysis. Flow cytometry is then used to confirm or exclude the diagnosis of PNH.
For patients with significant disease manifestations attributable to hemolysis, including disabling fatigue, transfusion-dependence, frequent pain paroxysms, worsening renal insufficiency, thrombosis, or other end-organ complications, it is recommend anticomplement therapy with eculizumab (Grade 1A).
Thrombotic stroke in a young woman with history of spontaneous abortions
A 28-year-old woman was admitted with a minor stroke due to a
cerebrovascular thrombosis. She had had four spontaneous abortions in the
past. She was a non-smoker. Cerebral angiography confirmed the thrombosis
but showed normal vasculature otherwise. Haemoglobin, platelet and
white-cell counts were normal. Antibodies to nuclei, extractable nuclear antigens and
double-stranded DNA were negative, but she did have high-titre anticardiolipin
antibody and a positive test for lupus anticoagulant. She was initially treated
with low-dose aspirin; once a diagnosis of primary antiphospholipid antibody
syndrome was made, she received long-term anticoagulant therapy.
Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met Clinical criteria
1. Vascular thrombosis, one or more clinical episodes of arterial or venous thrombosis, in any tissue or organ. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature (stroke and transient ischemic attack) is the most common site for arterial thrombosis.
2. Pregnancy morbidity (spontaneous abortions). These complications include fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, and/or multiple embryonic losses (<10 weeks gestation)
Laboratory criteria:persistent laboratory evidence of antiphospholipid antibodies
1. Positive test result for lupus anticoagulant
2. Anticardiolipin antibody of IgG and/or IgM isotype
3. Anti-beta-2 glycoprotein-I antibody of IgG and/or IgM isotype
*
Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met Clinical criteria
1. Vascular thrombosis, one or more clinical episodes of arterial or venous thrombosis, in any tissue or organ. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature (stroke and transient ischemic attack) is the most common site for arterial thrombosis.
2. Pregnancy morbidity (spontaneous abortions). These complications include fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, and/or multiple embryonic losses (<10 weeks gestation)
Laboratory criteria:persistent laboratory evidence of antiphospholipid antibodies
1. Positive test result for lupus anticoagulant
2. Anticardiolipin antibody of IgG and/or IgM isotype
3. Anti-beta-2 glycoprotein-I antibody of IgG and/or IgM isotype Other manifestations of APS include
• Thrombocytopenia is frequently observed in APS patients. The degree of thrombocytopenia is usually moderate.
• Patients with APS may develop various lung manifestations including pulmonary thromboembolic disease, thromboembolic and non-thromboembolic pulmonary hypertension (pulmonary arterial hypertension).
• Cardiac manifestations of APS most commonly involve the valves, including valvular thickening, and valve nodules (also referred to as nonbacterial vegetations or Libman-Sacks endocarditis) which can lead to valvular dysfunction.
• Livedo reticularis is the most common cutaneous manifestation of APS.
• Acute or chronic renal failure with proteinuria. Patient with lupus and antiphospholipid antibodies with livedoreticularis (manifested by a reddish-cyanotic, reticular pattern of the skin) which has resulted in ulcer formation (arrows).
La proteina C è una proteina che possiede attività anticoagulante ed assieme alla proteina S e antitrombina III, ha il compito di contrastare l’eccessiva funzione dell’attività coagulativa mantenendo fluido il sangue. In alcuni pazienti è presente una variazione geneticamente determinata dal fattore V della coagulazione (fattore V di Leiden) che ostacola l’attività anticoagulante della proteina C; questo fenomeno è evidenziato dal test della Resistenza alla Proteina C Attivata (aPCR). L’aPCRè associata ad un aumentato rischio trombo embolico.
Pathways of homocysteine metabolism
Homocysteine is metabolized by one of two divergent pathways: transsulfuration and remethylation. Thetranssulfuration of homocysteine to cysteine is catalyzed by cystathionine-β-synthase (CBS), a process that requires pyridoxal phosphate (vitamin B6) as a cofactor.
Remethylationof homocysteine produces methionine. This reaction is catalyzed either by methionine synthase or by betaine-homocysteine methyltransferase. Vitamin B12 (cobalamin) is the precursor of methylcobalamin, which is the cofactor for methionine synthase.
DISCOID RASH
MALAR RASH PHOTOSENSITIVITY ORAL AND NASOPHARYNGEAL ULCERS
NON-EROSIVE ARTHRITIS Asymmetrical oligoarthritis Symmetrical polyarthritis SEROSITIS Pericardial effusion Pleural effusion Pericarditis chest pain Pleuritic chest pain
Several forms of
glomerulonephritis
may occur, including mesangial, focal
proliferative, diffuse proliferative, and
membranous. Some patients may also
have
interstitial nephritis
.
The urine often contains white cells (95%), red cells, and white cell casts. Eosinophiluria is neither very sensitive nor specific.
A 30 year old woman presents with episodic joint painand stiffness of both hands for 1 year, which affects her activities of daily living. There is no morning stiffness and she is well in-between episodes. She also complains of developing oral ulcers recently. Her medical, drug and obstetric histories are unremarkable. Plain radiographs of both hands and feet are found to be normal.
Very Rash
Select Relevant Investigations
Autoantibody Screen
ANA titer: 1:80 (normal <1:40) Anti-dsDNA antibodies: positive
Anti-Ro Antibodies: Negative Anti-La Antibodies: Negative Rheumatoid Factor: Negative Anti-CPA: Negative
Full Blood Count
WBC/DC: 3,500/mm3 N: 57%, L: 29%
Hb: 10.1 g/dL Platelets: 79,000/mm3
Urinalysis and Renal Functions
Appearance: clear Pus Cells, RBC, Cell Casts: nil/hpf
Urea: 4.5 mmol/L (2.5-6.7) Creatinine: 0.9 mg/dl (0.8-1.4)
ESR + CRP Performed
ESR: 80 mm/1h (< 15)
CRP: 0.8 ng/ml (< 6)
Select Relevant Management
• Rituximab
• Sun Screen
• Hydroxychloroquine
Diagnosis and reasoning
The field of rheumatology encompasses diseases not merely of the joints, but also autoimmune and connective tissue diseases with arthritic manifestations.
Most of these affect women more than men; thus, the young woman presenting with joint pain is not an uncommon occurrence in general practice.
In many such cases, a history and examination that focuses on the chronology and disease course, distribution and symmetry of the affected joints, presence or absence of inflammation, and extraarticular manifestations is sufficient to reach a probable diagnosis.
This 30 year old lady has presented with a 1 year history of episodic joint pain and stiffness of the hands; the chronicity gives preference to an inflammatory cause, rather than an acute infection or a self limiting etiology.
Examination reveals the presence of symmetrical peripheral polyarticular involvement, exclusively of hand joints, with evidence of inflammation.
Also noteworthy in the assessment is the presence of extra-articular features such as oral ulcers and skin rashes.
Note that arthritis, oral ulcers and discoid rashes satisfy three of the eleven diagnostic criteria for SLE, making this a plausible diagnosis; the presence of an elevated ESR but normal CRP are further supportive of this.
However, Rheumatoid Arthritis (RA), Sjogren’s Syndrome and Psoriatic Arthritis (symmetrical polyarthritis type) remain possibilities - not only as the primary disease, but also as components of overlap syndrome (i.e. features of SLE as well as another connective tissue disease).
Early RA can be extremely difficult to differentiate from SLE, as both diseases can cause a symmetrical peripheral polyarthritis, and as both may predominantly involve the proximal interphalangeal (PIP) joints.
While the absence of morning stiffness is a point against RA, it does not definitively exclude this possibility; note also that the absence of rheumatoid nodules, or radiographic changes, does not rule out RA either, as these are features of late disease.
The absence of sicca symptoms, which is the hallmark of Sjogren’s syndrome, makes this condition clinically less likely. Psoriatic Arthritis can present as a symmetric peripheral polyarthritis; when considered along with the presence of a rash, this possibility might be considered - but note that the rash is discoid, rather than the characteristic plaques of Psoriatic Arthritis.
Thus, SLE takes precedence over the other differentials. A focused investigation panel to satisfy the diagnostic criteria and definitively exclude the other diseases should be the next step, starting with a full blood count and antibody screen.
In this patient, the presence of anemia and lymphocytic leukopenia with thrombocytopenia, and the high ANA titers and positive Anti-dsDNA antibodies fulfil 3 more of the diagnostic criteria for SLE, confirming the clinical diagnosis. Note also that the absence of anti-RO and anti-LA antibodies definitively excludes Sjogren’s Syndrome; the normal x-ray of the hands shows no erosive changes which might suggest at Psoriatic Arthritis.
The negative rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) assays provide further evidence against RA, as one or both of these are positive in 50% to 80% of such patients.
As SLE is a multisystemic disease, these patients should be screened for involvement of the other organs - particularly the kidneys.
In this patient, the normal urinalysis and renal function test in this patient make lupus nephritis less likely at the moment, but these tests should be repeated biyearly.
A customized treatment plan is necessary for each patient based on symptom manifestations, organ involvement, and disease severity.
In general, patients with arthritis and skin manifestations are considered to have milder disease; thus, flares are often controlled with NSAIDS and low potency medications such as hydroxychloroquine.
Proper sun protection with an effective sunscreen is advisable in patients with skin manifestations.
Immunosuppressive agents such as Methotrexate and biological therapies such as rituximab, an anti-CD20 monoclonal antibody, are reserved for patients with severe disease which has not responded to conventional treatment; therefore, these are not indicated right now.
THERAPY
• The goals of therapy for systemic lupus erythematosus(SLE) patients are to ensure long-termsurvival, achieve the lowest possible disease activity, preventorgan damage, minimizedrug toxicity, improvequality of life, andeducate patientsabout their role in disease management. • Determining the appropriate therapeutic regimen requires an accurate assessment of both disease activity and severity, and a clear
understanding of the patient’s response to previous therapeutic interventions. The three general patterns of disease to consider when assessing disease activity include*intermittent disease flares (or relapsing and remitting disease),*chronically active disease, and*quiescent disease.
• In clinical practice, disease activity and severity are assessed using a combination of clinical history, physical examination, laboratory and imaging studies for specific organs, and serologic tests.
• We typically check the following laboratory tests when monitoring disease activity in patients with SLE: complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), spot urine protein and creatinine, serum creatinine, estimated glomerular filtration rate (eGFR), anti-double-stranded deoxyribonucleic acid (dsDNA), and complement levels (C3 and C4).
• Several nonpharmacologic and preventive interventions important in the management of SLE include sun protection, diet and nutrition, exercise, smoking cessation, maintenance of appropriate immunizations, treatment of comorbid conditions, avoidance of specific medications, avoidance of radiation, and pregnancy and contraception counseling.
• The therapeutic approach to SLE is highly individualized and is guided by the predominant disease manifestations. However, some general principles of drug therapy for all SLE patients are as follows:
• Among patients with SLE with any degree and type of disease activity, we suggest administering hydroxychloroquine or chloroquine (Grade 2B), unless a contraindication exists.
• Additional therapy is based upon the severity of disease and the combination of manifestations:
• Patients with mild lupus manifestations (eg, skin, joint, and mucosal involvement) are administered hydroxychloroquine or chloroquine, with or without nonsteroidal antiinflammatory drugs (NSAIDs), and/or short-term use of low-dose glucocorticoids (eg, ≤7.5 mg prednisone equivalent per day).
• Patients with moderate lupus involvement are defined as having significant but non-organ-threatening disease (eg, constitutional, cutaneous, musculoskeletal, or hematologic).Patients usually respond to hydroxychloroquine or chloroquine plus short-term therapy with 5 to 15 mg of prednisone (or equivalent) daily. Prednisone is usually tapered once hydroxychloroquine or chloroquine has taken effect. A steroid-sparing immunosuppressive agent (eg, azathioprine or methotrexate) is often required to control symptoms.
• Patients with severe or life-threatening manifestations secondary to major organ involvement (eg, renal and central nervous system)
generally require an initial period of intensive immunosuppressive therapy (induction therapy) to control the disease and halt tissue injury. Patients are usually treated for a short period of time with high doses of systemic glucocorticoids (eg, 1 to 2 mg/kg/day of prednisone or equivalent or intermittent intravenous “pulses” of methylprednisolone) used alone or in combination with other immunosuppressive agents (eg, mycophenolate, cyclophosphamide, or rituximab). This initial therapy is subsequently followed by a longer period of less intensive, and ideally less toxic, maintenance therapy to consolidate remission and prevent flares. During this phase of treatment, the dose of prednisone or equivalent is reduced while monitoring clinical and laboratory measures of disease activity.
PROGNOSIS
●SLE can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease with fulminant organ failure and death. Clinical remission after appropriate therapy is uncommon, and when it is achieved, it is often not sustained.
●Poor prognostic factorsfor survival in SLE include renal disease (especially diffuse proliferative glomerulonephritis), hypertension, male sex, younger or older age at presentation, low socioeconomic status, black race, presence of antiphospholipid antibodies, and high overall disease activity.
●Patients with SLE have mortality rates ranging from 2 to 5 times higher than that of the general population. The major causes of death in the first few years of illness are active disease (eg, central nervous system [CNS] and renal) or infection due to immunosuppression, while causes of late death include complications of SLE (eg, endstage renal disease), treatment complications, and cardiovascular disease. Patients are also at risk for significant morbidity due to both active disease and the side effects of drugs such as glucocorticoids and cytotoxic agents.
●Although the overall risk of death due to malignancy does not appear to be increased in SLE patients, the risk of death due to specific malignancies, particularly non-Hodgkin lymphoma, is significantly increased among SLE patients when compared with the general population.
Reynaud’s phenomenon in a patient with dysphagia
A 41-year-old African American woman with no significant medical history presented to clinic reporting
of episodic finger numbness and colour changes. She described feeling as if her fingers were frostbitten
and noted her second, third and fourth digits appeared white distally. She additionally reported of
occasionally feeling food stuck in her throat after consuming solids. Physical examination revealed no
joint abnormalities or evidence of skin tightening. Laboratories revealed a creatinine level of 0.95 mg/dL
and trace proteinuria. An antinuclear antibody test was positive at 1:1200 and anticentromere
antibody was also positive. The diagnosis of limited cutaneous systemic sclerosis (lcSSc) was performed
on the basis of the patient's symptoms and aforementioned serology. Her dysphagia was concerning for
oesophageal dysmotility and required gastroenterology follow-up.
Raynaud's phenomenon (RF) features a triphasic colour response as fingertips change colour in response
to perfusion changes. Initial vasospasm results in pale white fingertips, followed by blue discolouration
secondary to circulatory stasis, and, finally, red appearance in the setting of reperfusion. While primary RP
occurs without associated disease and is classically a benign condition, secondary RP is associated with a
wide variety of diseases including scleroderma, systemic lupus erythaematous and other autoimmune
diseases, cryoglobulinaemia, hypothyroidism, sympathomimetic drug use and paraneoplastic syndrome.
Calcium channel blockers, PDE-5 inhibitors, and prostacyclins such as beraprost sodium and iloprost, for
symptomatic control of RP.
Gli
anticorpi anti-ENA
sono autoanticorpi antinucleo diretti contro
antigeni nucleari estraibili (ENA) e sono presenti in numerose malattie
autoimmuni
Questi sono:
• Anticorpi
anti-RNP
specifici della connettivite mista (100% dei casi), ma
presenti anche nel lupus eritematoso sistemico (25-40%), nella
sclerodermia e nell'artrite reumatoide;
• Anticorpi
anti-Smith,
presenti in un terzo dei casi di lupus;
• Anticorpi
anti-SS-A (o anti-Ro)
e
anti-SS-B (o anti-La)
, caratteristici della
sindrome di Sjögren (50-70%), ma presenti anche nel lupus;
• Anticorpi
anti-Scl-70 (o anti-topoisomerasi-1)
, caratteristici della forma
diffusa con coinvolgimento polmonare della sclerodermia;
• Anticorpi
anti-Jo1
, presenti nella polimiosite (15-35%);
• Anticorpi
anti-PM1,
tipici della polimiosite associata a sclerodermia (60%);
• Anticorpi
anti-centromero
, presenti nella sindrome CREST (90%) e nella
• AC ANTI-ACA IgG (Anti-Cardiolipina) Metodo EIA AC ANTI-ACA IgM (Anti-Cardiolipina) Metodo EIA • AC ANTI-AMA (Anti-Mitocondri) Metodo IFI
• AC ANTI-ANA (Anti-Nucleo) Metodo IFI su Hep2
• AC ANTI-ANCA (Anti-Citoplasma dei Neutrofili) Metodo IFI Se test IFI positivo, segue la determinazione di Ac. anti MPO e Ac. anti PR3 (metodo EIA)
• AC ANTI-APCA (Anti-Cellule Parietali Gastriche) Metodo IFI • AC ANTI-ASA (Anti-Epidermide) Metodo IFI
• AC ANTI-ASCA (Anti-Saccharomyces Cerevisiae) ASCA IgA Metodo EIA, ASCA IgG Metodo EIA • AC ANTI-ASMA (Anti-Muscolo Liscio) Metodo IFI
• AC ANTI-BETA2 GLICOPROTEINA IgG Metodo EIA AC ANTI-BETA2 GLICOPROTEINA IgM Metodo EIA • AC ANTI-CCP (Anti-Citrullina) Metodo EIA
• AC ANTI-CENTROMERO Vedi AC ANTI-ANA • AC ANTI-EMA IgA (Anti-Endomisio) Metodo IFI
• AC ANTI-ENA (Anti-Antigeni Nucleari Estraibili) Metodo EIA qualitativo. Test di screening: se positivo, si esegue il seguente profilo:Ac anti U1 RNP, Ac anti SmD, Ac anti SSA/Ro, Ac anti SSB/La, Ac anti CENP-B, Ac anti Scl 70, Ac anti Jo 1,
• AC ANTI-ENA-PM (Anti-Antigeni Nucleari Estraibili Polimiosite) Metodo Immunoblot: Ac anti Jo 1, Ac anti Ro-52, Ac anti Ku, Ac anti Mi 2, Ac anti PL-7, Ac anti PL-12,Ac anti PM-Scl100, Ac anti Pm-Scl75, Ac anti SRP, Ac anti EJ, Ac anti OJ
• AC ANTI-ENA-SCL (Anti-Antigeni Nucleari Estraibili Sclerodermia) Metodo Immunoblot Si esegue il seguente profilo: Ac anti Scl-70, Ac anti CENP-A, Ac anti CENP-B, Ac anti RP-11, Ac anti RP-155, Ac anti-Fibrillarina, Ac anti NOR90, Ac anti Th/To, Ac anti PM-Scl100, Ac anti PM-Scl75, Ac anti Ku, Ac anti PDGFR, Ac anti Ro-52
• AC ANTI-GAD (Acido Glutammico Decarbossilasi)
• AC ANTI-GBM (Anti-Membrana Basale Glomerulare) Metodo EIA • AC ANTI- IA2
• AC ANTI-INSULINA
• AC ANTI-LC1 (Anti-Citosol Epatico Tipo 1)
• AC ANTI-LKM (Anti-Microsomi Epatici Renali) Metodo IFI • AC ANTI-MPO (Anti-Mieloperossidasi) Metodo EIA
• AC ANTI-nDNA (Anti-DNA Nativo) Ac anti n-DNA Metodo EIA Se positivo si esegue test IFI Ac anti n-DNA Metodo IFI • AC ANTI-PR3 (Anti-Proteinasi 3) Metodo EIA
• AC ANTI-RECETTORI TSH
• AC ANTI-SLA (Anti-Antigene Epatico Solubile) Metodo Immunoblot • AC ANTI-TIREOGLOBULINA
• AC ANTI-TPO (Tireoperossidasi)
RA = rheumatoid arthritis;
SLE = systemic lupus erythematosus;
SSc = systemic sclerosis.
SpA = spondyloarthropathy (primarily ankylosing spondylitis);
SS = Sjögren’s syndrome;
PULMONARY INVOLVEMENT IN SYSTEMIC SCLEROSIS
Pulmonary involvement in systemic sclerosis is the leading cause of death.
• Interstitial Lung Disease
• Pulmonary Hypertension (pulmonary vascular disease)
• Recurrent aspiration
Telangiectasias are small dilated blood vessels near the surface of the skin
or mucous membranes, measuring between 0.5 and 1 millimeter in
diameter. They can develop anywhere on the body but are commonly seen
on the face around the nose, cheeks, and chin. They can also develop on
the legs, specifically on the upper thigh, below the knee joint, and around
the ankles.
SCLERODERMA RENAL CRISIS
• In patients with early diffuse scleroderma
• Pathogenesis (non-inflammatory): obliterative vasculopathy, luminal narrowing of small renal arteries, progressive reduction in renal blood flow, juxtaglomerular hyperplasia, increased renin secretion, activation of angiotensin, further renal vasoconstriction (vicious cycle → accelerated hypertension).
• Presentation: accelerated hypertension, oliguric renal insufficiency, thrombotic thrombocytopenia, microangiopathic hemolysis
• Therapy: angiotensin converting enzyme inhibitors (even in the presence of progressive renal dysfunction and dialysis).
A patient with dry mouth and dry eyes who developed polyarthritis
A 38-year-old woman was referred to an oral surgeon for investigation of a dry
mouth. She had a sister with arthritis. Examination and investigations were
unremarkable except for a raised ESR (42mm/h). Six months later, she developed a
mild conjunctivitis and complained of sore eyes. On testing, rheumatoid factor was
now positive (Rose-Waaler titre 1/64); total serum proteins were raised (98g/l); and
immunoglobulin levels showed a raised IgG of 28g/l (NR 7.2-19.0), with a slightly
raised IgM of 2.8g/l (NR 0.5-2.0) and a normal IgA. Schirmer's test was performed.
The test was markedly abnormal as only 3.5mm of the filter strip in the right eye
and 1.5mm of that in the left eye became wet.
She was treated with methylcellulose eye drops to prevent corneal ulceration. Over
a period of many years, her rheumatoid factor titre steadily increased and ANA and
antibodies to the extractable nuclear antigens Ro and La became detectable.
Seven years after the development of the dry mouth and dry eyes (together known
as the sicca complex), she developed a mild, bilateral non-erosive polyarthritis of
her hands, wrists and knees. A diagnosis of Sjogren’s syndrome was made. The
disease has remained mild. Non-steroidal anti-inflammatory drugs have been given
for the arthritis but have had no effect on the sicca complex.
Gli
anticorpi anti-ENA
sono autoanticorpi antinucleo diretti contro
antigeni nucleari estraibili (ENA) e sono presenti in numerose malattie
autoimmuni
Questi sono:
• Anticorpi
anti-RNP
specifici della connettivite mista (100% dei casi), ma
presenti anche nel lupus eritematoso sistemico (25-40%), nella
sclerodermia e nell'artrite reumatoide;
• Anticorpi
anti-Smith,
presenti in un terzo dei casi di lupus;
• Anticorpi
anti-SS-A (o anti-Ro)
e
anti-SS-B (o anti-La)
, caratteristici della
sindrome di Sjögren (50-70%), ma presenti anche nel lupus;
• Anticorpi
anti-Scl-70 (o anti-topoisomerasi-1)
, caratteristici della forma
diffusa con coinvolgimento polmonare della sclerodermia;
• Anticorpi
anti-Jo1
, presenti nella polimiosite (15-35%);
• Anticorpi
anti-PM1,
tipici della polimiosite associata a sclerodermia (60%);
• Anticorpi
anti-centromero
, presenti nella sindrome CREST (90%) e nella
I coloranti oftalmici sono un gruppo di sostanze impiegate in oftalmologia a fini diagnostici. La colorazione vitale con fluoresceina sodica o rosa bengala e' usata abitualmente nella diagnosi delle patologie corneali e congiuntivali.
La fluoresceina e' correntemente usata per dimostrare i difetti dell'epitelio corneale ed emette una luce verde quando e' illuminata con un filtro cobalto. Aree di lesione dell'epitelio corneale o congiuntivale presenteranno una captazione della fluoresceina apparendo di colore verde brillante.
La colorazione con rosa bengala evidenziera' le cellule epiteliali morte o degenerate della cornea e della congiuntiva (incluso il nucleo e la parete cellulare). Puo' anche colorare il muco del film lacrimale precorneale ed e' particolarmente utile nella diagnosi e nella valutazione della cheratocongiuntivite secca. E' evidente infatti la correlazione fra intensita' della colorazione e gravita' della alterazioni a carico delle cellule.
•ACUTE INFLAMMATORY SALIVARY GLAND DISORDERS • Sialadenitis
• Sialolithiasis
•CHRONIC INFLAMMATORY & INFILTRATIVE DISORDERS •SALIVARY GLAND TUMORS
A 32-year-old woman with a past history of ulcerative colitis (quiescent for the
last 7 years), presented with a dry cough. The cough became productive of
clear sputum and she was admitted 2 months later with increasing dyspnoea,
arthralgia, myalgia and progressive proximal, symmetrical muscle weakness .
A clinical diagnosis of fibrosing alveolitis was made and confirmed by
transbronchial biopsy. She was treated with prednisolone, which proved her
arthralgia, and it became clear that she had a severe proximal myopathy.
Serum creatine kinase was found to be very high and a muscle biopsy showed
necrosis and a cellular infiltrate compatible with polymyositis. She had a
circulating autoantibody to Jo1 antigen .
She recovered eventually, after a stormy course which included treatment with
pulsed methylprednisolone, oral azathioprine and three plasma exchanges of
2.5 litres. She has persistent myalgia and some arthralgia and remains on
20mg prednisolone daily.
Idiopathic Inflammatory Myopathies • Polymyositis • Dermatomyositis • Inclusion Body Myositis
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A 32-year-old man from a Turkish family presented with deteriorating vision and painful
swollen knees. Further questioning revealed a 10-year history of relapsing and remitting
mouth ulcers and a less severe history of genital ulceration. On examination he had
reduced visual acuity associated with a florid retinal vasculitis. Two 1-cm mouth ulcers
were found but no active genital ulceration. He had synovitis in both knees. Investigation
revealed a raised erythrocyte sedimentation rate at 94mm/h but a normal blood count
and negative tests for rheumatoid factor, antinuclear antibodies, cytomegalovirus and HIV
infection. A clinical diagnosis of Behcet’s syndrome was made. He was treated with
high-dose corticosteroids and cyclosporin with good response, although his visual acuity
remains permanently impaired.
A 19-year-old typist presented with acute, bilateral arthralgia of her hands, wrists and
knees. The pain prevented her from sleeping or typing. On examination, there were no
effusions or tenderness of any joints. No diagnosis was made but she was treated
symptomatically with indomethacin. Two years later, she developed a mild degree of
Raynaud's phenomenon, with a flare-up of the arthralgia and some proximal muscle
weakness. On investigation, she had a low haemoglobin (10.8g/l) but a normal white-cell
count and differential. Her ESR was raised (63mm/h), and her serum contained ANA (titre
1/160; speckled pattern). dsDNA binding was normal but antibodies to ENA were detected
and found to be largely directed against nuclear ribonucleoprotein (RNP); there were no
antibodies to the Sm antigen. A latex test for rheumatoid factor was negative. Complement
levels (C3 and C4) were normal but she had a raised serum IgG of 21.8g/l (NR 7.2-19.0).
X-rays of the hands and knees were normal. There was no proteinuria and her serum
creatinine and blood urea were normal.
A diagnosis of mixed connective tissue disease was made and the patient started on a low
dose of prednisolone. The pain in her wrists and knees improved dramatically, but attempts
to reduce and discontinue the steroids were unsuccessful; severe arthritis returned each
time the drug was discontinued. Her Raynaud's phenomenon has slowly worsened and is
now associated with progressive sclerodactyly.
A patient with dry mouth and dry eyes who developed polyarthritis
A 38-year-old woman was referred to an oral surgeon for investigation of a dry
mouth. She had a sister with arthritis. Examination and investigations were
unremarkable except for a raised ESR (42mm/h). Six months later, she developed a
mild conjunctivitis and complained of sore eyes. On testing, rheumatoid factor was
now positive (Rose-Waaler titre 1/64); total serum proteins were raised (98g/l); and
immunoglobulin levels showed a raised IgG of 28g/l (NR 7.2-19.0), with a slightly
raised IgM of 2.8g/l (NR 0.5-2.0) and a normal IgA. Schirmer's test was performed.
The test was markedly abnormal as only 3.5mm of the filter strip in the right eye
and 1.5mm of that in the left eye became wet.
She was treated with methylcellulose eye drops to prevent corneal ulceration. Over
a period of many years, her rheumatoid factor titre steadily increased and ANA and
antibodies to the extractable nuclear antigens Ro and La became detectable.
Seven years after the development of the dry mouth and dry eyes (together known
as the sicca complex), she developed a mild, bilateral non-erosive polyarthritis of
her hands, wrists and knees. A diagnosis of Sjogren’s syndrome was made. The
disease has remained mild. Non-steroidal anti-inflammatory drugs have been given
for the arthritis but have had no effect on the sicca complex.
A 32-year-old woman with a past history of ulcerative colitis (quiescent for the
last 7 years), presented with a dry cough. The cough became productive of
clear sputum and she was admitted 2 months later with increasing dyspnoea,
arthralgia, myalgia and progressive proximal, symmetrical muscle weakness .
A clinical diagnosis of fibrosing alveolitis was made and confirmed by
transbronchial biopsy. She was treated with prednisolone, which proved her
arthralgia, and it became clear that she had a severe proximal myopathy.
Serum creatine kinase was found to be very high and a muscle biopsy showed
necrosis and a cellular infiltrate compatible with polymyositis. She had a
circulating autoantibody to Jo1 antigen .
She recovered eventually, after a stormy course which included treatment with
pulsed methylprednisolone, oral azathioprine and three plasma exchanges of
2.5 litres. She has persistent myalgia and some arthralgia and remains on
20mg prednisolone daily.
Diagnosis Distinguishing features Infection
Viral infection Fever, respiratory or gastrointestinal symptoms, viral diagnostic testing Bacterial infection Hypotension, rash, heart murmur, leukocytosis, bacteremia
Spirochetal infection Rash, Lyme or RPR serology Noninflammatory pain syndrome
Fibromyalgia Tender points, nonrestorative sleep, normal test results Chronic fatigue syndrome, also known as systemic exertion intolerance disease Longstanding, profound fatigue without other explanation Systemic rheumatic disease and autoinflammatory disease
Polymyalgia rheumatica Acute onset of proximal myalgia, morning stiffness, over age 55, high ESR, prompt improvement with low-dose glucocorticoids Polymyositis/dermatomyositis Proximal weakness, rash, elevated CK, myopathic EMG, muscle histology
Rheumatoid arthritis Chronic, symmetric polyarthritis, positive RF, and/or anti-cyclic citrullinated peptide antibody Systemic lupus erythematosus Polyarthritis, rash, nephritis, serositis, positive ANA antibody, anti-double-stranded DNA antibody, and/or anti-Smith antibody Spondyloarthropathy History of psoriasis, colitis, conjunctivitis, urethritis, low back pain
Vasculitis Multisystem inflammatory disease, palpable purpura, paresthesias, focal neurologic deficit, cavitary pulmonary nodules, active urinary sediment, positive ANCA Metabolic
Osteomalacia Reduced 25-hydroxy vitamin D
Metabolic myopathy Exercise intolerance, family history, muscle weakness, muscle biopsy results Scurvy Petechiae, ecchymoses, follicular hyperkeratosis, corkscrew hairs, vitamin C deficiency Endocrinologic
Familial Mediterranean fever Episodic fever, serositis, arthralgia, abdominal pain, onset during childhood Neuropathic Paresthesias, focal neurologic deficits
Hypothyroidism Elevated TSH, decreased free T4
Adrenal insufficiency Low-serum cortisol, 24-hour urine cortisol, and/or abnormal ACTH stimulation test Medications History of new medication use, especially statins
Psychiatric Prior history of mood disorder, depressed affect
Idiopathic Inflammatory Myopathies • Polymyositis • Dermatomyositis • Inclusion Body Myositis
PMR: Polymyalgia rheumatica INTERSTITIAL LUNG FIBROSIS
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*
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*
*
*
Anti-Jo 1
CK
GOTTRON’S PAPULES LUNG CANCERA 32-year-old man from a Turkish family presented with deteriorating vision and painful swollen knees. Further questioning revealed a 10-year history of relapsing and remitting mouth ulcers and a less severe history of genital ulceration. On examination he had reduced visual acuity associated with a florid retinal vasculitis. Two 1-cm mouth ulcers were found but no active genital ulceration. He had synovitis in both knees. Investigation revealed a raised erythrocyte sedimentation rate at 94mm/h but a normal blood count and negative tests for rheumatoid factor, antinuclear antibodies, cytomegalovirus and HIV infection. A clinical diagnosis of Behcet’s syndrome was made. He was treated with high-dose corticosteroids and azathioprine with good response, although his visual acuity remains permanently impaired.
Criterion Required features Recurrent oral
ulceration Aphthous (idiopathic) ulceration, observed by clinician or patient, with at least three episodes in any 12-month period Plus any two of the following:
Recurrent genital
ulceration Aphthous ulceration or scarring, observed by clinician or patient
Eye lesions Anterior or posteriorretinal vasculitisdocumented by ophthalmologistuveitiscells in vitreous in slit-lamp examination; or
Skin lesions Erythema nodosum-like lesions observed by clinician or patient; papulopustularskin lesions or pseudofolliculitis with characteristic acneiform nodules observed by clinician
Pathergy test Interpreted at 24 to 48 hours by clinician
