Hanna Przepiera-Będzak Klinika Reumatologii PAM, Szczecin

1. Hanna Przepiera-Będzak Klinika Reumatologii PAM, Szczecin

2. SYSTEMIC LUPUS ERYTHEMATOSUS • autoimmune disease expressed in both localized cutaneous and systemic multiorgan forms • characterized by humoral and cellular immunologic abnormalities that lead to tissue destruction through the deposition of immune complexes and autoantibodies

3. ETIOLOGY The exact etiology of LE remains unknown Factors contributing to the development of disease ·exposure to ultraviolet ·ancillary viral infections ·psychological stress ·Certain medications: procainamide, hydralazine (can lead to a drug-induced lupuslikesyndrome) ·women are much more likely to have lupus than men (in adults- ratio 10:1; in both prepubertal and postmenopausal - ratio 2:1 or 3:1.) ·black, Asian, and Native American groups have a higher prevalence of lupusthan do whites. ·genetic markers that are associated with SLE the class I major histocompatibility complex (MHC) molecule HLA-B8 the class II MHC molecules HLA-DR2 and HLA-DR3 deficiencies of complement components (class III MHC molecules), specially the absence of C2 or C4 or the presence of the C4A null allele

4. SYSTEMIC LUPUS ERYTHEMATOSUSINCIDENCE AND EPIDEMIOLOGY • incidence among white females two to three per 100,000 and among black females seven to eight per 100,000. • prevalence vary between one and ten per 10,000 in the general population one per 100 among family members of patients

5. SYSTEMIC LUPUS ERYTHEMATOSUSCLINICAL FEATURES Systemic lupus is a multisystemic disease for which the diagnosis rests on the identification of a constellation of clinical findings with supportive laboratory tests. No single finding or test result confirms the diagnosis. However, some findings, such as a characteristic malar rash or discoid lesions or high titers of antibodies to double-stranded DNA or antibodies to the Sm antigen, in the context of a systemic illness are more suggestive than others. Criteria for the identification and classification of patients as having SLE suitable for clinical studies have been formulated by the American Rheumatism Association

7. SYSTEMIC LUPUS ERYTHEMATOSUSCONSTITUTIONAL FINDINGS ·fever (fever due to infection must be differentiated from fever due to SLE. Acute severe LE may be accompanied by fever above 40 °C, but sustained fever above 39.5 °C is not common) ·fatigue ·anorexia, ·nausea, ·weight loss

8. SLE -CUTANEOUS FINDINGS ·Acute cutaneous lupus: facial (malar or butterfly) erythema involving the bridge of the nose and the cheeks, often with extension to the chin and ears. It heals without scarring, although telangiectasia may occur. More extensive erythema, either palpable or nonpalpable, may involve the arms and trunk, predominantly in sun-exposed areas (exacerbated by exposure to ultraviolet light) Widespread morbilliform or bullous eruption. ·Subacute cutaneous lupus: superficial, nonscarring papulosquamous or annular lesions of the trunk with a widespread and symmetrical distribution (exacerbated by exposure to the sun) The involved skin may become hypopigmented and telangiectatic. ·Chronic cutaneous lupus: discoid skin lesions, which are erythematous, raised, scaling patches most commonly found on the head and scalp. They are characterized by follicular plugging, atrophic central scarring, depigmentation, and telangiectasia

12. SYSTEMIC LUPUS ERYTHEMATOSUSMUSCULOSKELETAL FINDINGS • arthralgia (arthritis presents classically as nonerosive, nondeforming polyarthritis with symmetrical involvement of the proximal interphalangeal joints, metacarpophalangeal joints, wrists, and knees) • myalgia. Muscle weakness may reflect general malaise, (sub)clinical myopathy, or overt inflammatory myositis. Electromyographic abnormalities are more common than elevations in the creatine kinase value; muscle biopsy may show myositis with fiber damage and inflammatory cells or a vacuolar myopathy. Muscle weakness may also reflect a corticosteroid-induced myopathy, a chloroquine - induced myopathy, or a myasthenia gravis-like syndrome in addition to direct involvement of muscle by LE.

13. SLE-CARDIOVASCULAR FINDINGS • Pericarditis is the most common manifestation. Effusions demonstrable by echocardiography are present in more than half of patients, whereas symptomatic disease occurs in one fourth to one third of patients. Tam-ponade rarely occurs. • Myocardial disease secondary to muscle inflammation or small vessel involvement can cause conduction defects and myocardial dysfunction leading to congestive heart failure. • Verrucous endocarditis (Libman-Sacks syndrome) rarely leads to clinically important valvular lesions or embolic complications. • Peripheral vascular manifestations include small vessel vasculitis, phlebothrombosis with or without thrombophlebitis, thrombosis without vasculitis, and, rarely, gangrene. • Raynaud's phenomenon occurs in one fourth of patients. • Accelerated atherosclerosis with early myocardial infarction and myocardiopathy is increasingly recognized as a cause of significant morbidity in LE patients, especially in those treated with glucocorticoids for long periods.

14. SLE - PULMONARY FINDINGS ·Pleuritis is the most common pulmonary finding of LE. Pleural effusions occur in up to half the patients, whereas pleuritic pain is reported by at least two thirds. ·Abnormal results of pulmonary functions tests with both restrictive and obstructive deficits occur more frequently than radiologically overt interstitial fibrosis. • Acute "lupus pneumonitis" may be extensive or more limited with only patchy infiltrates and platelike atelectasis on the chest film. Progression to acute pulmonary insufficiency with intrapulmonary hemorrhage is infrequent. Lupus pneumonitis is a diagnosis of exclusion; as with many other manifestations of LE, infection must be rigorously excluded.

15. SLE RENAL FINDINGS deposition of immunoglobulin in glomeruli is probably very common, but only about half of SLE patients have clinically evident nephritis with proteinuria, hematuria, and/or cylindruria. In lupus nephritis the entire range of glomerular pathologic lesions (mesangial, membranous, proliferative, and membranoproliferative) as well as interstitial abnormalities have been reported. SLE nephritis manifests as: • proteinuria (>0.5 g/24 h or >3+ by nonquantitative measures), • casts (including RBC, granular, tubular, mixed, and heme), • hematuria (>5 RBCs per high-power field [HPF]), • pyuria (>5 WBCs per HPF in absence of infection), • and/or elevated serum creatinine.

16. SLE - NEUROLOGIC FINDINGS • seizures and psychiatric dysfunction, which may range to overt psychosis. ·organic brain syndrome, both extrapyramidal and cerebellar dysfunction, optic neuritis, and aseptic meningitis as well as tissue infarcts and subarachnoid hemorrhage. ·headaches, which may resemble migraine · peripheral nervous system involvement cranial nerve palsies, transverse myelitis with paraparesis or quadriparesis, and sensory or sensorimotor neuropathies. · depression and anxiety

17. SLE - HEMATOLOGIC FINDINGS • Anemia is common and related mainly to acute and chronic inflammatory disease. However, other causes include renal insufficiency, blood loss, hemolysis, or adverse effects of medications. • Leukopenia, and especially lymphopenia, are features of active SLE in about 20-30% of patients. The leukopenia generally is mild, 2500-4000, and rarely below 1500. • Thrombocytopenia occurs in approximately 20% of patients with lupus and generally follows the course of acute lupus and responds to treatment. However, a subset of patients has more severe and persistent thrombocytopenia, which may require alternative treatments, including intravenous immunoglobulin and splenectomy. Some of these latter patients have antiphospholipid antibodies.

18. SLE – LABORATORY FINDINGS • Acute phase reactants, ESR and C-reactive protein, may be elevated in active SLE, but they are not reliable markers of disease activity. • Liver function tests may be mildly elevated with acute SLE and may reach very high levels with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially salicylates. • Serum creatinine kinase may be elevated in patients with SLE and myositis and patients with overlap syndromes. • Complement levels (C3, C4, CH50) may be depressed in patients with active SLE due to consumption by active immune complex–induced inflammation. This is observed in patients with both renal and extrarenal involvement.

19. SLE - Autoantibody testing • ANA is a useful screening test because ANAs are present in more than 95% of patients, but it is not diagnostic of the disease in the absence of an appropriate clinical presentation. • Antibodies to DNA histones are responsible for the LE cells. They are common in SLE but are characteristically the only type of ANA observed in patients with drug-induced lupus due to procainamide or hydralazine. • The test for antibodies to dsDNA (anti-dsDNA) is highly specific for SLE but has lower sensitivity than ANA, with about 70% incidence depending on the technique employed. Levels may correlate with disease activity, particularly with SLE nephritis. • Anti-Sm also is highly specific for SLE but is observed in only 30-40% of patients. Levels tend to remain stable throughout the disease course, and its presence is not a definite marker for any specific manifestation.

20. SLE - Autoantibody testing • Antibodies to SSA/Ro and SSB/La are observed in 15-20% of patients with SLE. They are observed in other connective tissue diseases also, including Sjögren syndrome, but interest in them stems from their correlation with certain SLE features, especially subacute cutaneous lupus rashes. They also are found in the mothers of babies with neonatal lupus syndromes—skin rash, congenital heart block—even though 50% of those mothers have no clinical disease. • Antibodies to ribosomal P protein are uncommon in SLE but do correlate with the presence of lupus cerebritis. • Antiphospholipid antibodies are associated with livedo reticularis, arterial and venous thrombosis without vasculitis or active SLE, an increased incidence of fetal wastage (including midtrimester and late abortions and stillbirths), and thrombocytopenia. Different types of antiphospholipid antibodies can be detected by a number of different laboratory tests.

22. American College of Rheumatology (ACR) Criteria for the Classification of SLE • Malar rash • Discoid rash • Photosensitivity (skin) • Oral ulcers (oral or nasopharyngeal, usually painless) • Arthritis (nonerosive) • Serositis (pleurisy, pericarditis) • Renal involvement (proteinuria, cellular casts) • Neurologic disorder (seizures, psychosis) • Hematologic disease (leukopenia, thrombocytopenia, lymphopenia) • Immunologic disorder (lupus erythematosus [LE] cells; anti-DNA; anti-Smith [anti-Sm]; biologic false-positive [BFP] serologic test for syphilis [STS], antiphospholipid antibodies) • ANA

23. SLE - DRUG TREATMENT PREDNISONE (Deltasone, Orasone, Meticorten) - Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. • oral 60-80 mg/day • pulse i.v. methylprednisolone 500-1000 mg /day 2-3 days HYDROXYCHLOROQUINE (Plaquenil) -- Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

24. SLE - DRUG TREATMENT AZATHIOPRINE (Imuran) - Immunosuppressant and less toxic alternative to cyclophosphamide in therapy of nephritis and as steroid-sparing agent in nonrenal disease. Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.Dose 100mg/day CYCLOPHOSPHAMIDE - pulse i.v. 500 mg-1 g /weekly for 3 weeks followed by monthly pulses for 3-12 months (+ MESNA to eliminate cystitis) - oral 100-200 mg/day 10-days/20 day

25. ANTIPHOSPHOLIPID ANTIBODY (APL) SYNDROME the clinical constellation of: ·venous and arterial thrombosis ·recurrent fetal loss ·thrombocytopenia associated with the occurrence of autoantibodies with an apparent specificity for anionic phospholipids

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32. ANTIPHOSPHOLIPID ANTIBODY (APL) SYNDROMELABORATORY anticardiolipin antibody: IgG, IgM anti B2GP1antibody lupus anticoagulant prolongation of APTT  

33. SJÖGREN’S SYNDROME chronic autoimmune rheumatic and lymphoproliferative disease characterized by a progressive lymphocytic and plasma cell infiltration of the salivary and lacrimal glands leading to xerostomia (dry mouth), salivary gland swelling and xerophtalmia (dry eyes) Primarily affects women 40-50 years (F:M ratio 9:1) PRIMARY SJÖGREN’S SYNDROMESECONDARY SJÖGREN’S SYNDROME:accompanying RA or other connective tissue disease

34. SJÖGREN’S SYNDROME • Sicca syndrome • Keratoconjunctivitis - Dry eyes with reduced tear production with gritty or sandy sensation under the lids; red eyes; photosensitivity • Xerostomia - Decreased saliva production leading to difficulties with chewing, swallowing, and even speech; abnormality in taste and smell; dental caries; mucosal burning sensation; sensitivity to spicy and acidic foods and beverages; increased risk for oral candidiasis; hoarseness of voice • Musculoskeletal symptoms • Arthralgia, morning stiffness, nonerosive arthritis • Myalgia, muscle weakness • Cutaneous findings • Raynaud phenomenon • Nonthrombocytopenic purpura, especially of lower extremities • Nasal, vaginal, and cutaneous dryness

35. SJÖGREN’S SYNDROME • Gastrointestinal symptoms • Dysphagia, nausea, epigastric pain • Achalasia (in children) • Achlorhydria, chronic atrophic gastritis • Primary biliary cirrhosis • Pulmonary findings • Dyspnea due to mild interstitial disease • Dry cough • Renal findings - Interstitial nephritis • Other symptoms - Fatigue, depression

36. SJÖGREN’S SYNDROMEPhysical examination • Parotid gland enlargement • Corneal ulceration, vascularization • Vasculitic lesions - Purpura • Lymphadenopathy • Autoimmune thyroiditis • Neuromuscular manifestations • Peripheral sensorimotor neuropathy • CNS disorders, such as movement disorder, transverse myelopathy, encephalopathy, aseptic meningitis, and dementia, have been described in some studies.

37. SJÖGREN’S SYNDROME Physical examination • Arthritis • Intermittent synovitis • Chronic nonerosive polyarthritis: Jaccoud arthropathy is observed in adults. • Oral cavity • Mild erythema and thinning of the mucosa • Erythema, fissuring, coating, and depapillation of the dorsal tongue • Traumatic erosions and ulcers, angular cheilitis, and chapped lips • Frothy, ropey, and thickened saliva

38. SJÖGREN’S SYNDROMELABORATORY • Mild anemia and leukopenia are present. • Erythrocyte sedimentation rate (ESR): Elevated ESR is observed in 80-90% of patients; however, C-reactive protein (CRP) usually is within the reference range. • Immunoglobulin levels: Hypergammaglobulinemia, up to several grams of immunoglobulin G (IgG), is observed in 80% of patients. • Autoantibodies • Antinuclear antibody (ANA) and rheumatoid factor (RF) - Usually elevated • Anti-Ro (SS-A), anti-La (SS-B) • Other autoantibodies to thyroglobulin, thyroid microsomal, mitochondrial, smooth muscle, and salivary duct • Rose Bengal staining: The dye stains the damaged corneal epithelium and indicates keratoconjunctivitis.

39. SJÖGREN’S SYNDROMEImaging Studies • Sialography - A sensitive and specific radiographic technique to find evidence of sialectasis • Technetium Tc 99 pertechnetate scintigraphy - Delayed uptake in Sjögren syndrome, and correlates with pathological changes • Magnetic resonance imaging (MRI) - Visualization of the glandular parenchyma, in particular for the evaluation of cystic or solid masses (In addition, the volumetric estimate of the gland size can be determined.)

40. SJÖGREN’S SYNDROMEOther Tests • In the questionnaire forsalivary hypofunction, positive responses to all 4 of the following questions indicate major salivary gland hypofunction (adapted from Fox and others, 1998). • Do you sip liquids to aid in swallowing dry foods? • Does your mouth feel dry when eating a meal? • Do you have difficulties swallowing any foods? • Does the amount of saliva in your mouth seem to be too little? • Schirmer tear test: This test is used to evaluate tear production by lacrimal glands. A strip of filter paper is placed beneath the lower lid, and wetting of the paper is measured at 5 minutes. Less than 5 mm of wetting suggests decreased tear production.

41. SJÖGREN’S SYNDROMEOther Tests • Salivary gland biopsy • The pathological findings are very useful in diagnosis. • Because of the relative ease and lack of complications, labial minor salivary gland biopsy is preferred over parotid gland biopsy, which can result in facial nerve damage. • In order to ensure that a representative sample has been obtained for histopathologic examination, harvesting 5-10 lobules of minor salivary glands is important.

42. SJÖGREN’S SYNDROMEMedical Care • Xerostomia - Stimulation of salivary flow with sialagogues, such as pilocarpine or cevimeline; mechanical stimulation through the use of sugarless chewing gum or lozenges; topical tissue hydration or lubrication from drinking water or the use of artificial saliva • Oral hygiene • Keratoconjunctivitis - Artificial tears

43. POLYMYOSITIS chronic inflammatory disease of skeletal muscle characterised by symmetrical weakness of proximal limb girdle muscles as well as of the trunk, neck, and pharyngeal musculature. When a rash is also present, the term DERMATOMYOSITIS is used

44. POLYMYOSITISETIOLOGY AND PATHOGENESIS • the cause -unknown. • serum antibodies directed against certain nuclear and cytoplasmic proteins : anti-Jo 1, anti-PM-Scl, and anti-RNP, • polymyositis has occurred in several patients with hypogammaglobulinemia, • the relationship to malignancy should be considered • infectious agents Influenza B1 virus infection echovirus, coxsackievirus B1 antigens Toxoplasma gondii • there is a 2:1 female predominance

45. POLYMYOSITISCLINICAL FEATURES • Proximal muscle - the onset of weakness is usually insidious, and it primarily affects the hip and/ or shoulder girdle and neck flexors. Inability to rise from a squatting or kneeling position or from a low chair, to climb stairs, and to raise arms above one's head are common early complaints that progress over a period of weeks or months • Pharyngeal muscles: dysphagia, difficulty swallowing liquids with nasal regurgi-tation, aspiration into the tracheobronchial tree, and dysphonia. • Weakness in the distal extremities (forearm, hand, leg, foot) is less common (25%), • Muscle pain, aching, or tenderness on palpation may be present in up to half of patients but is usually mild. • Late findings include atrophy with wasting, joint contractures

46. POLYMYOSITIS chronic inflammatory disease of skeletal muscle characterised by symmetrical weakness of proximal limb girdle muscles as well as of the trunk, neck, and pharyngeal musculature. When a rash is also present, the term DERMATOMYOSITIS is used

47. POLYMYOSITIS /DERMATOMYOSITISETIOLOGY AND PATHOGENESIS • the cause -unknown. • serum antibodies directed against certain nuclear and cytoplasmic proteins : anti-Jo 1, anti-PM-Scl, and anti-RNP, • polymyositis has occurred in several patients with hypogammaglobulinemia, • the relationship to malignancy should be considered • infectious agents Influenza B1 virus infection echovirus, coxsackievirus B1 antigens Toxoplasma gondii • there is a 2:1 female predominance

48. POLYMYOSITIS /DERMATOMYOSITISCLINICAL FEATURES • Proximal muscle - the onset of weakness is usually insidious, and it primarily affects the hip and/ or shoulder girdle and neck flexors. Inability to rise from a squatting or kneeling position or from a low chair, to climb stairs, and to raise arms above one's head are common early complaints that progress over a period of weeks or months • Pharyngeal muscles: dysphagia, difficulty swallowing liquids with nasal regurgi-tation, aspiration into the tracheobronchial tree, and dysphonia. • Weakness in the distal extremities (forearm, hand, leg, foot) is less common (25%), • Muscle pain, aching, or tenderness on palpation may be present in up to half of patients but is usually mild. • Late findings include atrophy with wasting, joint contractures

49. POLYMYOSITIS /DERMATOMYOSITISCLINICAL FEATURES • Cutaneous involvement may precede, accompany, or follow muscle weakness. classic facial rash (10%-15% of patients) - affects the upper eyelids and face with edema and has a lilac or heliotrope color • Red, scaly patches (Gottron's papules) are found over the extensor surfaces of the elbows, knees, and small joints of the hands and may be pruritic. • Nailfolds show periungual erythema, thickening, and gross telangiectatic changes