Systemic Autoimmunity

Transcription

1 Systemic Autoimmunity Carol A. Langford, MD, MHS Harold C. Schott Chair Director, Center for Vasculitis Care and Research Department of Rheumatic and Immunologic Diseases Cleveland Clinic

2 Disclosure Research Grant : Genentech, Bristol-Myers Squibb A range of different diseases are discussed and many referenced therapeutic agents are approved for the indication. For some diseases, there are few to no approved therapies; some unlabeled uses of therapeutic agents are identified and discussed.

3 Educational Objectives Systemic Autoimmunity Upon completion of this session, participants should be able to: Identify forms of systemic autoimmune diseases that are encountered by the allergist/immunologist Describe clinical manifestations of systemic autoimmune diseases that could present to the allergist/immunologist Explain the diagnostic approach to systemic autoimmune diseases, including autoantibodies Recognize therapeutic options used in systemic autoimmune diseases

4 Systemic Autoimmunity Systemic Autoimmunity and Systemic Autoimmune Disease What to cover? American Board of Allergy and Immunology Systemic Autoimmune Disease Rheumatoid arthritis Systemic lupus erythematosus Vasculitis Other Disorders Sjögren s syndrome Inflammatory myositis Scleroderma

5 Rheumatoid Arthritis Diagnosis Epidemiology Chronic inflammatory disease of unknown etiology characterized by a symmetric, peripheral polyarthritis Inflammation of the joint synovium results in destruction of cartilage and bone Systemic disease with extraarticular manifestations Prevalence 1% of the population The most common form of chronic inflammatory arthritis Incidence increases between ages 25-55, plateaus until 75 decreases 2-3 Female:Male

6 Rheumatoid Arthritis Articular disease Clinical Manifestations Earliest involved joints small joints hands and feet Early AM stiffness lasting > 1 hour Stiffness lessens with use and worsens with inactivity ( gel ) Key findings on examination: Location - small and medium sized joints Findings swelling, warmth, and tenderness Number typically a polyarthritis (> 5 joints) Pattern typically symmetrical In well established RA Most commonly involved joints wrists, MCP, PIP

7 Rheumatoid Arthritis Articular disease Clinical Manifestations Early Rheumatoid Arthritis Symmetrical swelling DIP, MCP wrist Soft tissue swelling Synovial proliferation Late Rheumatoid Arthritis Ulnar deviation Subluxation of MCP Erosion cartilage and bone Displacement of tendons, ligaments

8 Rheumatoid Arthritis Articular disease Clinical Manifestations Joint damage Juxtaarticular osteopenia Symmetric joint space loss Subchondral marginal erosions

9 Rheumatoid Arthritis Articular disease Clinical Manifestations

10 Rheumatoid Arthritis Extraarticular disease Clinical Manifestations Occur in ~40% of patients over their lifetime Risk factors for extrarticular disease (+) RF Smoking Early onset disability Marker of disease severity Associated with increased morbidity and premature mortality Successful treatment linked with control of underlying joint disease

11 Rheumatoid Arthritis Extraarticular disease Clinical Manifestations Pulmonary Interstitial lung disease Organizing pneumonia Pleural effusions (exudative) Nodules Cardiac Ischemic heart disease Pericarditis Cardiomyopathy Arrhythmia

12 Rheumatoid Arthritis Extraarticular disease Clinical Manifestations Hematologic Felty s syndrome (+) RF, neutropenia, splenomegaly Anemia of chronic disease Large granular lymphocyte Lymphoma (2-4 fold increased risk) Eye Scleritis (5%) Episcleritis Uveitis Secondary Sjögren s

13 Rheumatoid Arthritis Extraarticular disease Clinical Manifestations Skin Rheumatoid nodules Pyoderma gangrenosum Purpura Vasculitis Skin Nerve GI Eye

14 Rheumatoid Arthritis Diagnosis Laboratory features Markers of inflammation CBC: normocytic normochromic anemia, thrombocytosis Low serum albumin Increased ESR, CRP Rheumatoid factor - IgM anti-igg Sensitivity: 70% Specificity: 80% Negative result does not rule out disease (sero-negative RA) Nonspecific: also seen in the elderly, chronic infections (hepatitis C), other chronic inflammatory diseases High titers predict more severe disease course (extraarticular features) Antibodies to cyclic citrullinated peptide (anti-ccp) Sensitivity ~ 70% in RA Specificity 95% Predictive of worse outcomes (erosive disease, rapid progression)

15 Rheumatoid Arthritis Diagnosis 2010 ACR / EULAR Classification Criteria Aletaha D, et al. Arthritis Rheum 2010; 62: Target population of at least 1 swollen joint not explained otherwise Goal : early diagnosis Distinguish patients at the onset of disease with a high likelihood of evolving into a chronic disease with joint damage Score based algorithm: RA 6 of a possible 10 Joint involvement 1 large joint large joints small joints ( large jts) small joints ( large jts) 3 > 10 joints (at least 1 small) 5 Serology Negative RF and ACPA (CCP) 0 Low pos RF or low pos ACPA 2 High pos RF or ACPA 3 Acute phase reactants Normal CRP and ESR 0 Abnormal CRP or ESR 1 Duration of symptoms < 6 weeks 0 6 weeks 1

16 Rheumatoid Arthritis Goals: Decrease pain Improve function Reduce inflammation Prevent structural damage Early diagnosis and intervention Initiate treatment to accomplish remission or low disease activity Change or escalate medications for persistent active disease Treatment Outcome Assessment of disease activity Variety different tools (DAS28, SDAI, CDAI, RAPID3, PAS) Joint swelling, joint tenderness, acute phase Evidence of joint damage (imaging) Presence of extraarticular features

17 Rheumatoid Arthritis Conventional DMARD (Disease Modifying Anti-Rheumatic Drugs) Treatment Outcome Agent Methotrexate Hydroxychloroquine Sulfasalazine Leflunomide (Minocycline) Main side effects Hepatotoxicity, cytopenia, pneumonitis Retinal damage cardiotoxicity, blood dyscrasia Granulocytopenia, hemolytic anemia (G6PD) Hepatotoxicity Skin discoloration Methotrexate (MTX) used in almost all DMARD regimens in patients without contraindications Triple combination therapy MTX + hydroxychloroquine + sulfasalazine RACET trial as effective as MTX+ etanercept (O Dell et al. NEJM 2013;369:307)

18 Rheumatoid Arthritis TNF inhibitors Treatment Outcome Agent Etanercept Infliximab Adalimumab Golimumab Certolizumab Agent construct Soluble fusion protein TNF receptor + human IgG1 Chimeric monoclonal AB Humanized monoclonal AB Humanized monoclonal AB Pegylated Fc-free fragment humanized monoclonal AB Side effects: Increased risk of bacterial and fungal infections Reactivation of latent TB (screening important) Drug-induced lupus Neurologic deficits Cardiac failure (avoid in patients with low EF) Possible increase in lymphoma

19 Rheumatoid Arthritis Non-TNF Biologics Treatment Outcome Agent Abatacept Anakinra Rituximab Tocilizumab Mechanism of Action CTLA4-Ig inhibits T cell costimulation IL1 receptor antagonist Anti-CD20 depletes B cells Anti-IL6 receptor Blocks IL6 Small molecule inhibitor Agent Tofacitinib Mechanism of Action Janus kinase (JAK) inhibitor

20 Rheumatoid Arthritis 2012 ACR RA Treatment Guidelines Treatment Outcome Singh, JA, et al. Arthritis Care and Research 2012; 64: Key concepts of the guidelines: Treat to target (remission or low disease state) Treatment is changed/escalated for lack of response Early (< 6 months) vs late disease Good vs poor prognosis Functional limitations, erosions, sero-positive, extraarticular disease Addresses co-morbidities (TB, malignancy, CHF) Addresses that there are medication choices/options

21 Rheumatoid Arthritis 2012 ACR RA Treatment Guidelines Treatment Outcome Singh, JA, et al. Arthritis Care and Research 2012; 64: Early RA Low Moderate Disease Activity High Poor prognosis: Functional limitations Extraarticular disease (+) RF or anti-ccp Bony erosions by xray Features of Poor Prognosis Features of Poor Prognosis Without Without With With DMARD Monotherapy Combination DMARD DMARD Monotherapy or HCQ+MTX Anti-TNF +/- MTX or combination DMARD

22 Rheumatoid Arthritis 2012 ACR RA Treatment Guidelines Treatment Outcome Singh, JA, et al. Arthritis Care and Research 2012; 64: Low Activity Without PP Established RA Low Activity with PP or Mod/High Activity DMARD Monotherapy Reassess* Add MTX, HCQ, LEF Reassess* MTX Mono or Combination DMARD Reassess* Add/switch another DMARD Reassess* If serious adverse event Add /switch to anti-tnf Reassess or non-serious AE* Add/switch to ABA or RIT Reassess or any AE Switch to non TNF biologic Switch to anti-tnf or non-tnf biologic Reassess* Switch to another type or category and anti-tnf or non-tnf biologic *Every 3 months

23 Rheumatoid Arthritis Outcome Treatment Outcome No reliable way to predict clinical course very heterogeneous disease Natural history impacted by age of onset, sex, genotype, phenotype, comorbid conditions 10% will have a spontaneous remission within 6 months Majority persistent and progressive disease that waxes and wanes but that is treatment responsive (particularly in modern day) Rare very aggressive form of RA with inexorable progression Overall mortality rate in RA 2 times greater than general population Most common cause of death ischemic heart disease, infection Median life expectancy shortened by 7 years men, 3 years women High risk poor outcome: extraarticular disease, low functional capacity, low socioeconomic class, low education, chronic prednisone use

24 Systemic Lupus Erythematosus Diagnosis Epidemiology Autoimmune disease of unknown etiology in which organs undergo injury by tissue binding antibodies and immune complexes. Systemic disease with prominent organ-threatening manifestations USA prevalence per 100,000 More common in African-Americans and women Caucasian female 164 per 100,000 African-American female 406 per 100,000 65% occur between ages can occur in all ages

25 Systemic Lupus Erythematosus Cutaneous (80%) Clinical Manifestations Photosensitivity Malar rash Oral ulcers Alopecia Discoid rash Vasculitis

26 Systemic Lupus Erythematosus Musculoskeletal (95%) Clinical Manifestations Arthralgias/myalgias Non-erosive polyarthropathy (Jaccoud s) Hematologic (80%) Leukopenia (< 4000/ l) Lymphopenia (< 1500/ l) Anemia (chronic) Hemolytic anemia Thrombocytopenia (< 100,000/ l) Lymphadenopathy Splenomegaly Antiphospholipid syndrome (clotting, miscarriages)

27 Systemic Lupus Erythematosus Neurologic (60%) Clinical Manifestations Cognitive disorder Mood disorder (including psychosis) Headache Seizures Mono- poly-neuropathy Stroke, TIA Cardiopulmonary (60%) Serositis Pleural effusions Pericardial effusions Pneumonitis Myocarditis Endocarditis (Libman-Sacks) Early cardiovascular mortality

28 Systemic Lupus Erythematosus Renal (30-50%) Weening et al. Kidney Int 200; 65:521 Clinical Manifestations One of leading causes of mortality Asymptomatic detected by urinalysis (proteinuria, hematuria, casts) Biopsy useful in diagnosis and planning treatment Immune complex glomerulonephritis Full-house immunofluorescence (IgG, IgA, IgM, C3, C1q) Immune deposits by electron microscopy Histologic class influences treatment and prognosis Class I: Minimal mesangial Class II: Mesangial proliferative Class III: Focal lupus nephritis (< 50% of glomeruli) Class IV: Diffuse lupus nephritis (> 50% of glomeruli) Class V: Membranous lupus nephritis Class VI: Advanced sclerotic lupus nephritis

29 Systemic Lupus Erythematosus Diagnosis Laboratory features Basic labs are in many ways the most important CBC can see low WBC, RBC, and platelets Renal function Urinalysis ESR and/or CRP Complement levels C3 and C4 often low Can reflect disease activity in some patients ANA (antinuclear antibodies) Present in almost everyone who has SLE Can be seen in other settings Can be seen in healthy people

30 Systemic Lupus Erythematosus Diagnosis Autoantibodies in SLE Autoantibody ANA Anti-DNA Anti-Sm Anti-RNP Anti-Ro (SSA) Anti-La (SSB) Anti-histone Anti-phospholipid Significance Best screening test High-titers SLE specific Associated with nephritis Correlates with disease activity in some patients High specificity for SLE Non specific for SLE High titers associated with overlap features Associated with sicca syndrome Subacute cutaneous lupus Neonatal lupus Associated with sicca syndrome Neonatal lupus Drug-induced lupus Thrombosis, pregnancy morbidity

31 Systemic Lupus Erythematosus Diagnosis ACR Criteria for the Classification of SLE Tan et al. A&R 1882;25:1271 and Hochberg et al. A&R 1997;40:1725. Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal Neurological (seizures or psychosis without other cause) Hematological (hemolytic anemia, leukopenia, thrombocytopenia) Immunological (anti-dna, anti-sm, and/or anti-phospholipid) ANA > 4 of 11 - Dx of SLE likely Specificity ~95%, Sensitivity ~75%

32 Systemic Lupus Erythematosus Treatment based on site of involvement and disease severity Cutaneous or musculoskeletal disease Hydroxychloroquine Should be given to almost all SLE patients Treatment for: cutaneous, articular disease May also: Reduce relapses Reduce accrual of disease related damage over time Requires annual eye examinations Treatment Outcome Belimumab (anti-blys) FDA approved for SLE Studied in those with musculoskeletal or cutaneous disease Best applied in those who require prednisone, failed other approaches No data in renal, CNS, or other severe disease features

33 Systemic Lupus Erythematosus Life or organ threatening disease Treatment Outcome Glucocorticoids Cyclophosphamide Severe SLE - CNS lupus, severe proliferative nephritis Proliferative nephritis (KDIGO. Kid Int 2012:2:209) Cyclophosphamide Well studied agent of proven benefit May still be preferred for those with high creatinine or crescents Mycophenolate mofetil (Appel et al. JASN 2009;20:1103) Some data suggests remission rate with MMF > CYC in African-Americans Remains limited longer-term data

34 Systemic Lupus Erythematosus Treatment Outcome Survival 95% at 5 years, 90% 10 years, 78% at 20 years Worse prognosis in American-Americans and Hispanic Americans Poor prognosis (50% mortality in 10 years) associated with: Elevated creatinine, hypertension, nephrotic syndrome Anemia, hypoalbuminemia, hypocomplementemia Male sex Ethnicity Leading causes of death: Active disease (nephritis) Infection Thomboembolic events Premature myocardial infarction

35 Sjögren s Syndrome Diagnosis Epidemiology Chronic autoimmune disease of unknown etiology characterized by lymphocytic infiltration of the exocrine glands resulting in keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth) 1/3 present with extraglandular features Primary Sjögren s Syndrome denovo disease Secondary Sjögren s Syndrome occurs with an underlying disease RA, SLE, scleroderma, MCTD, primary biliary cirrhosis Prevalence - Primary SS 0.5-1% Average age :1 Female:Male

36 Sjögren s Syndrome Eye Clinical Manifestations Keratoconjunctivitis sicca Gritty or sandy feeling Mouth Parotid enlargement Dry mouth (furrowed tongue) Tooth loss from increased decay

37 Sjögren s Syndrome Other exocrine features Clinical Manifestations Nasal dryness Xerotrachea Atrophic gastritis Vaginal dryness Extraglandular features Arthralgias/arthritis (60%) Raynaud s (37%) Lung disease (ILD)(14%) Lymphadenopathy Vasculitis Renal involvement (RTA) Liver involvement Peripheral nerve

38 Sjögren s Syndrome Diagnosis Laboratory features ESR elevation Hypergammaglobulinemia 22% Serologic abnormalities ANA 74% Anti-Ro/SSA 40% Anti-La/SSB 38% Rheumatoid factor 38% Biopsy features Lymphoid infiltrates of CD4+ lymphocytes (Differs from HIV CD8+ lymphocytes)

39 Sjögren s Syndrome Diagnosis International Classification Criteria for Sjogren s Syndrome Vitali et al. Ann Rheum Dis 2002; 61:554 I. Ocular symptoms II. Oral symptoms III. Ocular signs Schirmer s test < 5 mm in 5 minutes Rose Bengal or other ocular dye score IV. Histopathology in minor salivary glands Focal lymphocytic sialoadenitis V. Salivary gland involvement Unstimulated whole salivary flow Parotid scintigraphy Salivary scintigraphy VI. Antibodies to Ro/SSA or La/SSB or both 4 of 6 (must include either IV or VI) or 3 of either III, IV, V, VI

40 Sjögren s Syndrome Goals: Symptomatic relief Prevention of damaging local effects of secretion loss Treatment Outcome Eyes Avoidance of smoke, low humidity environment, drying medications Artificial tears Local stimulation cyclosporin drops Systemic stimulation pilocarpine, cevimeline Punctal plugs (blocking the lacrimal duct occlusion) Mouth Water Sugar free lozenge, gum Systemic stimulation pilocarpine, cevimeline Treatment of oral candidiasis Meticulous oral care and dental check-ups

41 Sjögren s Syndrome SS not associated with reduced survival Treatment Outcome Extraglandular features can be associated with mortality Lymphoma can occur in up to 6% Presents later in the disease course Extranodal, low grade marginal B cell lymphoma Suspect in persistent parotid enlargement, leukopenia

42 Inflammatory Myositis Diagnosis Epidemiology Chronic inflammatory diseases of muscle Three major groups: Polymyositis Dermatomyositis Inclusion body myositis Age at Onset > 18 Childhood and adult > 50 Overall prevalence: 1 in 100,000

43 Inflammatory Myositis Inclusion body myositis Age > 50 years, Male Clinical Manifestations Weakness, atrophy in distal muscles Dysphagia is common Histology vacuoles with lymphocytic infiltrates Generally treatment resistant Polymyositis and Dermatomyositis Muscle weakness typically not painful Difficulty holding head up (test neck flexors) Can affect muscles of breathing swallowing heart

44 Inflammatory Myositis Dermatomyositis Clinical Manifestations Skin features can precede or accompany muscle weakness Violaceous papules on knuckles (Gottron s sign) Purple discoloration on eyelids (heliotrope rash) Back and shoulders (shawl sign) Neck (V sign) Calcinosis

45 Inflammatory Myositis Diagnosis Laboratory features Elevated muscle enzymes CK and aldolase ANA 80% Anti-Jo1 Associated with antisynthetase syndrome Myositis Arthritis Obstructive lung disease Cracked, furrowed skin (Mechanics hands) EMG Can differentiate from neurogenic weakness Myopathic potentials short-duration, low amplitude, polyphasic units Spontaneous activity with fibrillations Complex repetitive discharges Positive sharp waves

46 Inflammatory Myositis Diagnosis Clinically suspected diagnosis confirmed by findings on: Muscle enzymes EMG Muscle biopsy Polymyositis T cell infiltrates within the muscle fascicle resulting in muscle fiber necrosis Dermatomyositis Inflammation perivascular or in the interfascicular septae Inflammation around rather than within the muscle fibers Perifascicular atrophy

47 Inflammatory Myositis Goals: Improve muscle strength Ameliorate extramuscular manifestations Treatment Outcome Glucocorticoids foundation of treatment Other immunosuppressive agents used in 75% Methotrexate Azathioprine Hydroxychloroquine may benefit skin manifestations Used in refractory cases Rituximab IVIg Calcineurin inhibitors (tacrolimus, cyclosporin)

48 Inflammatory Myositis 5 year survival 95%, 10 year survival 84% Treatment Outcome Disease related causes of death: Pulmonary or cardiac complications Prognosis worse for those: severely affected at presentation significant dysphagia respiratory effects DM has a better prognosis in general than PM Onset of myositis (DM > PM) is associated with malignancy All patients newly dx with myositis should undergo age and sex appropriate malignancy screening and evaluation of any sxs or signs that could suggest an occult malignancy

49 Scleroderma (systemic sclerosis) Diagnosis Epidemiology Connective tissue disorder of unknown etiology functional and structural alterations in vascular beds and visceral organ dysfunction due to fibrosis Two subsets defined by pattern of skin involvement: Limited cutaneous SSc Diffuse cutaneous SSc Prevalence 286 per million Age of onset :1 Female predominance declines after menopause

50 Scleroderma (systemic sclerosis) Limited cutaneous SSc Clinical Manifestations Skin Insidious onset Finger (sclerodactly) Distal extremities Face Calcinosis Raynauds (99%) Esophageal dysmotility Sclerodactly Telangiectasia Pulmonary arterial hypertension (15%) Interstitial lung disease (35%) Primary biliary cirrhosis

51 Scleroderma (systemic sclerosis) Diffuse cutaneous SSc Clinical Manifestations Skin Rapid onset Starts at fingers, ascends from distal to proximal extremities Face, trunk Raynaud s (98%) Esophageal involvement (80%) Arthralgia Carpal tunnel syndrome Early pulmonary fibrosis (65%) Renal crisis (5-20%) Pulmonary arterial hypertension (15%) Cardiac involvement (12%)

52 Scleroderma (systemic sclerosis) Diagnosis Laboratory features Autoantibody ANA Anti-centromere Anti-Topoisomerase (Scl70) Anti-RNA polymerase III Significance Occur in almost all patients lssc, calcinosis, isolated PAH dssc, ILD dssc, extensive skin disease, renal crisis Biopsy features Renal biopsy (renal crisis) Not usually required for diagnosis Reduplication of elastic lamina Narrowing vascular umen

53 Scleroderma (systemic sclerosis) Treatment based on site of involvement and disease severity Skin thickening and calcinosis No currently effective treatment Renal crisis Key is having patients self monitor BP Avoid glucocorticoids (risk factor for renal crisis) If renal crisis occurs ACE inhibitors Treatment Outcome Raynaud s avoidance of triggers, calcium channel blockers, selective PDE5 inhibitors Interstitial lung disease Some studies suggest benefit of cyclophosphamide - role remains unclear Pulmonary hypertension endothelin-1 receptor antagonists, PDE5 inhibitors, prostanoids supportive agents: oxygen, diuretics

54 Scleroderma (systemic sclerosis) High rate of mortality for both lssc and dssc 5-8 fold higher than the general population 5 year mortality 10%, 10 year 18% Has improved since 1970 s Treatment Outcome Poor prognosis associated with: dssc Cardiac and/or GI involvement FVC < 50% predicted Pulmonary fibrosis Hypertension Leading causes of death: Pulmonary fibrosis Pulmonary hypertension Cardiac complications (Renal crisis mortality is now rare with the use of ACE inhibitors)

55 Acknowledgements