Systemic autoimmune diseases

Transcription

1 Systemic autoimmune diseases Péter Studinger MD PhD Semmelweis University, First Department of Medicine 27/11/2017

2 Systemic autoimmune diseases: overview Systemic lupus erythematosus (SLE) Progressive systemic sclerosis (PSS) Sjögren syndrome (SS) Polymyositis, dermatomyositis (PM / DM) Epidemiology Pathogenesis Clinical features / diagnostic procedure Treatment options

3 Systemic autoimmune diseases: epidemiology SLE PSS SS PM/DM Prevalence: (/ ) Incidence: (/ person years) (Cooper et al. Autoimmunity Rev. 2003) Prevalence per

4 Systemic autoimmune diseases: epidemiology SLE geographical / racial distribution

5 Systemic autoimmune diseases: epidemiology Gender distribution (percent female): SLE 88% PSS 92% SS 94% PM/DM 67% Age at onset (mean or median): SLE 40 yrs PSS 50 yrs SS 59 yrs PM/DM 52 yrs SLE: 65% yrs, 20% - < 16 yrs 15% - > 65 yrs

6 Systemic autoimmune diseases: pathogenesis Genetic predisposition (MHCII, non-mhc genes) Environmental factors UV exposure, infections drugs, hormonal effects Immune dysregulation (Mo, MF, PDC, Th, Tr, B, citokines, cell-cell contact) Pathogen autoantibody Clinical symptoms Target organ damage

7 Systemic autoimmune diseases: pathogenesis SLE: genetic factors: ~20% of susceptibility - high concordance (14-57%) in monozygotic twins - first-degree relative with SLE: 17-fold risk - GWAS: 50 loci that predispose to SLE - complement components - MHC (HLA DR2 and DR3) - genes involved in IFNa pathway, lymphocyte signaling, clearance of immune complexes hormonal factors: increased risk with estrogen-containing contraceptive pills early onset of menarche post-menopausal estrogen replacement

8 Systemic autoimmune diseases: pathogenesis SLE: environmental factors: EBV infection as triggering effect? UV - light Silica dust exposure Allergies to medications immune abnormalities: increase in circulating plasma cells helper (CD4+) T cells polyclonal activation of B cells, abnormal B cell signaling prolonged life of B cells decreased cytotoxic T cell and suppressor T cell function

9 Systemic lupus erythematosus Clinical features: Constitutional symptoms: fatigue (80-100%) fever (>50%) myalgia / muscle weakness weight change Skin / mucous membranes (80-90%): Malar rash nasolabial folds are spared

10 Systemic lupus erythematosus Bullous lupus Discoid lupus Photosensitivity

11 Systemic lupus erythematosus Non-scarring alopecia Oral ulcers Raynaud phenomenon

12 Systemic lupus erythematosus Joint involvement (>90%): Deforming arthritis in some cases: non-erosive arthritis migratory (gone within 24 hrs) short morning stiffness polyarticular, symmetrical most common: knees, carpal joints, PIP deformities are often reducible swan neck deformity

13 Systemic lupus erythematosus Hematologic abnormalities: Pancytopenia - anemia of chronic disease / autoimmune hemolytic anemia - leukopenia / lymphopenia - mild thrombopenia Thromboembolic disease arterial /venous thrombosis Neurologic abnormalities: - seizures - psychosis - mononeuritis multiplex - peripheral neuropathy - acute confusional state (in the absence of other causes)

14 Serositis Systemic lupus erythematosus Pleural effusion pleuritic pain / rubbing / pleural effusion Pericarditis ECG / rub / evidence of pericardial effusion Cardiac abnormalities Verrucous (Libman-Sachs) endocarditis Heart block of varying degrees (in neonatal lupus)

15 NON- PROLIFERATIVE PROLIFERATIVE Renal involvment Systemic lupus erythematosus

16 Systemic lupus erythematosus Isolated proteinuria / nephrotic syndrome Non-proliferative types: Class I minimal mesangial lupus nephritis Class V membranous lupus nephritis

17 Proliferative types: Systemic lupus erythematosus Isolated hematuria / nephritic syndrome / rapidly progressive glomerulonephritis Class II mesangial proliferative lupus nephritis Class III and IV focal proliferative and diffuse proliferative lupus nephritis

18 Systemic lupus erythematosus End-stage renal disease Class VI advanced sclerosing lupus nephritis

19 Immunfluorescence: Systemic lupus erythematosus granular distribution Full house pattern

20 Laboratory diagnosis: Systemic lupus erythematosus Routine lab test: anemia, leukopenia, thrombopenia increased creatinine / BUN (in proliferative renal involvement) hematuria, proteinuria, cellular casts typically normal CRP!!! ANA screen: anti-sm (specific, but not sensitive) anti dsdna, anti C1q Complement: decreased C3 and C4 in lupus nephritis Antiphospholipid antibodies: lupus anticoagulant, anti-cardiolipin

21 Systemic lupus erythematosus Diagnostic imaging: plain radiograph of swollen joints erosions are rarely seen renal ultrasonography diffdg. of kidney injury chest radiography suspected pleural effusion, interstitial lung disease echocardiography suspected pericardial involvment or endocarditis MRI: - focal neurologic deficits, cognitive dysfunction

22 Treatment Systemic lupus erythematosus Disease activity calculators SLEDAI score mild-to moderate flares skin, joint, mucosal constitutional symptoms vs. severe flares major organ involvement (renal, CNS) Mild disease hydroxychloroquin, NSAID, short-term low-dose glucocorticoid Moderate disease hydroxychloroquin, glucocorticoids, steroidsparing immunosuppression Severe disease high-dose systemic glucocorticoids + immunosuppressive agents (cyclophosphamide / MMF / rituximab) induction long-term immunosuppression (azathioprine) maintenance

23 Progressive systemic sclerosis Scleroderma disorders : heterogeneous group of conditions linked by the presence of thickened, sclerotic skin lesions General symptoms: Fatigue (76 percent) Loss of strength (68 percent) Sleep difficulties (66 percent) Stiff joints (74 percent) Pain (67 percent) Skin symptoms Diffusely puffy hands Shiny skin

24 Progressive systemic sclerosis Decreased oral aperture Teleangiectasia Salt and pepper hypo- and hyperpigmentation Digital necrosis

25 Progressive systemic sclerosis Calcinosis cutis

26 Progressive systemic sclerosis Limited (lcssc) Sclerodactyly Only acral skin involvement Diffuse (dcssc) Proximal skin involvement Subcutaneous calcinosis Raynaud phenomenon Esophageal dysmotility Teleangiectasia CREST-syndrome Pulmonary hypertension Frequent pulmonary, cardiac gastrointestinal and renal involvement Relatively good prognosis Poor prognosis

27 Progressive systemic sclerosis Organ involvement in diffuse PSS Diffuse alveolitis Scleroderma renal crisis thrombotic microangiopathy Watermelon stomach

28 Nailfold capillaroscopy A) normal B) Heterogenous shape, enlarged loops C) Dilated loops, hemorrhage D) Neoformation of capillary E) Irregular distribution

29 Progressive systemic sclerosis Laboratory diagnosis: Routine lab test: anemia (malabsorption? GI blood loss? iron deficiency?), creatinine cretin-kinase (associated myopathy / myositis?) ANA screen: positive anti-topoisomerase I (anti Scl-70) dcssc anti-centromere (ACA) lcssc anti-rna polymerase III dcssc Specific (>99%), but not too sensitive (20-50%) markers

30 Progressive systemic sclerosis Evaluation of pulmonary involvement HRCT - interstitial lung disease Doppler ultrasonography pulmonary arterial hypertension Evaluation of cardiac involvement Annual ECG and echocardiography Evaluation of renal involvement Regular measurement of blood pressure Assesment of GFR and proteinuria every 3 months

31 Progressive systemic sclerosis Treatment Circulatory system: Ca-channel inhibitors ACE inhibitors avoid beta blockers!! Pentoxyphyllin Prostacyclin Endothelin-1 receptor antagonists Phosphodiestrase inhibitors Immunomodifying treatment Methotrexate / MMF Cyclophosphamide, Azathioprine Plasmapheresis Photopheresis autologous HSCTx Avoid steroid!! ( give ONLY in case of myositis, alveolitis or pericarditis ) Antifibrotic treatment Anti-TGFbeta Colchicin IFN alpha rhu relaxin Problems: Heterogenous disease Disease severity / activity assessment lack of tools Innovative drugs applied only in late stages

32 Progressive systemic sclerosis Localized scleroderma: Morphea (en plaque) Linear scleroderma: en coup de sabre. Ivory-colored (porcelain white) plaque with violaceous borders (lilac ring). In late stage atrophy, depigmentation / hyperpigmentation.

33 Sjögren syndrome Chronic inflammatory autoimmune disorder, characterized by diminished lacrimal and salivary gland function ± extraglandular involvement Xerophthalmia and keratoconjunctivitis sicca Rose-Bengal stain devitalized tissues Schirmer test reduced tear production (< 5mm in 5 min)

34 Xerostomia dry mouth Sjögren syndrome dry tongue enlarged parotid gland caries

35 Extraglandular disease Sjögren syndrome Skin: Xerosis, Raynaud phenomenon, cutaneous vasculitis Joints: arthralgia (symmetric, intermittent, nonerosive, nondeforming) Muscles: proximal muscle weakness Respiratory tract: chronic bronchitis, interstitial lung diseaes Renal: chronic interstitial nephritis, renal tubular acidosis Nervous system: peripheral neuropathy

36 Extraglandular disease Sjögren syndrome Hematology: cytopenias, hypergammaglobulinemia non-hodgkin lymphoma persistent unilateral glandular swelling, especially when previous swelling has been transient or intermittent hard, nodular texture to the gland presence of cutaneous vasculitis or palpable purpura systemic features (malaise, weight loss, fever)

37 Sjögren syndrome Diagnosis (4/6 items or 3/4 objective items) Ocular symptoms Oral symptoms Objective evidence of ocular involvement (Schirmer test / Rose Bengal test) Histopathology: focal lymphocitic sialoadenitis in small salivary glands Salivary gland involvement detected by measurement of unstimulated salivary flow / parotid sialography / salivary scintigraphy Autoantibodies: anti-ro (SSA) or anti-la (SSB)

38 Treatment Xerostomia Sjögren syndrome maintain good hydration avoid sucrose /carbonated beverages use a humidifier artificial saliva topical stimulants (muscarinic agonists) regular preventive dental care Xerophthalmia: artificial teras topical cyclosporin topical steroids Extraglandular manifestations: Joint /skin : hydoxychloroquin / MTX Severe cardiopulmonary / neural involvement: steroid + cyclophosphamide

39 Polymyositis / dermatomyositis Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory myopathies, characterized by the shared features of proximal skeletal muscle weakness and by evidence of muscle inflammation. DM, unlike PM, is associated with a variety of characteristic skin manifestations.

40 Polymyositis / dermatomyositis Symmetrical proximal muscle weakness Elevated levels of skeletal muscle enzymes: CK, LDH, AST, ALT, Characteristic EMG Increased insertional activity and spontaneous fibrillations Abnormal myopathic low-amplitude, short-duration polyphasic motor unit potential Complex repetitive discharges

41 Polymyositis / dermatomyositis Muscle biopsy (m. biceps brachii /. m. quadriceps femoris): mononuclear cellular infiltration phagocytosis, necrosis degeneration and regeneration of muscle fibers Increased connective tissue DM: characteristic skin lesions

42 Polymyositis / dermatomyositis Skin involvement Gottron s papules: violaceous, scaly papules overlying the joints Gottron s sign: erythematous to violaceous patches

43 Skin involvement Polymyositis / dermatomyositis Heliotrope rash: Violaceous erythema on the upper lids and mid-facial erythema that does not spare the nasolabial folds Eyelid edema

44 Skin involvement Polymyositis / dermatomyositis Shawl sign eruptions of the upper back Mechanic s hand cracked, fissured hypertrophic changes

45 Polymyositis / dermatomyositis Extraskeletal involvement Esophagus dysmotility dysphagia, odynophagia, GERD Decreased bowel motility constipation Laryngeal involvement dysphonia Respiratory muscles dyspnea Cardiac muscles arrhythmias, heart failure, myocarditis Extramuscular involvement Arthralgia /arthritis: symmetrical, non-erosive, Raynaud-syndrome Interstitial lung disease Paraneuplastic dermatomyositis (RR: 3x) severe, therapy resistant skin symptoms CK may be normal General symptoms Subfebrility / fever, anorexia, weight loss, tiredness

46 Polymyositis / dermatomyositis Myositis-specific autoantibodies (30%): Antibodies to aminoacyl-transfer (t)rna synthetases (antisynthetase antibodies), including anti-jo-1 (20%) strong association with interstitial lung disease, Raynaud phenomenon, arthritis, and mechanic s hand Antibodies to signal recognition particle (SRP) (5%) severe myopathy, aggressive disease Antibodies to Mi-2, a nuclear helicase (5-30%) acute onset DM, good response to therapy

47 Treatment: Polymyositis / dermatomyositis Immunosuppressive therapy Corticosteroids (PM 50% nonresponsive, DM ~ 90% good response) improves strength preserves muscle function survival benefit? azathioprine, methothrexate (steroid-sparing agents) hydroxychloroquin (only skin disease), rituximab, cyclophosphamide, IVIG, MMF, calcineurin inhibitors in resistant disease Supportive therapy fiziotherapy