Rheumatology E-learning. University of Szeged Department of Rheumatology and Immunology

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Myra Warner
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1 Rheumatology E-learning University of Szeged Department of Rheumatology and Immunology

2 Rheumatoid arthritis Prevalence: 1:200 the most common chronic polyarthritis worldwide Female:male: 3:1 Peak incidence: years Clinical characteristics: Symmetric, chronic, inflammation, involving both the small- and large joints Erosive arthritis leads to progressive articular damage, functional deterioration and disability The characteristic involvement of the fingers and wrists Systemic signs premature death without appropriate treatment

Rheumatoid arthritis cartilage and bone destruction Normal synovial layer: a thin membrane of loosely associated fibroblast- and macrophagelike mesenchymal cells lining the articular

3 Rheumatoid arthritis cartilage and bone destruction Normal synovial layer: a thin membrane of loosely associated fibroblast- and macrophagelike mesenchymal cells lining the articular capsule Rheumatoid synovium: an agressively proliferating inflammatory tissue with several cell types and a huge overproduction of proinflammatory cytokines and tissuedegrading enzymes (=pannus)

4 Early rheumatoid arthritis Swelling of PIP (left) and MCP and PIP (below) joint lines

5 The hand in rheumatoid arthritis Early RA: Swelling and tenderness of the wrist, MCP and PIP lines but the DIP line is very rarely involved! Morning stiffness > 1 hour Fist formation is not complete Grasping force is decreased (unscrewing a cap, use of a hand, writing, etc.)

6 Longstanding RA Ulnar deviation of fingers Flexion contracture in the MCP joints Z-deformity ( hitch-hiker ) in the thumb Rheumatoid nodules

7 Chronic RA

8 The hand in rheumatoid arthritis Long-standing RA: Wrist movements are restricted. The ulnar head is hypermobile ( piano key sign ) or subluxed. Median nerve compression carpal tunnel syndrome I. MCP and PIP subluxation hitch-hiker deformity II-V. MCP: flexion contracture, ulnar deviation Interosseus muscle atrophy Boutonniére and swan neck deformity Ankylosis, subluxation, tendon rupture

9 Characteristic deformities in RA Boutonniére deformity Swan neck deformity

10 Characteristic deformities in RA Ulnar deviation + Flexion contracture in MCP

Erosions (arrow) bone defects next to the involved joints

11 Radiographic progression of damage in rheumatoid arthritis Linear osteoporosis around MCP and PIP joints early stage Erosions (arrow) bone defects next to the involved joints Joint space narrowing Deformities, subluxations, ankylosis final stage

12 Rheumatoid arthritis - foot Depressed transverse arch Hallux valgus Digitus malleus (hammer toe)

Atlanto-axial instability The intervertebrate joint between the 1st and 2nd vertebrae (atlas and axis) becomes unstable due to a degeneration of the dens and the loosening of the ligaments The spinal

13 Atlanto-axial instability The intervertebrate joint between the 1st and 2nd vertebrae (atlas and axis) becomes unstable due to a degeneration of the dens and the loosening of the ligaments The spinal cord or the medulla oblongata are compressed during extreme head movements May be fatal (cardio-respiratiory centre laesion, rupture of the spinal cord Caution: head movements, gymnastics, intubation, dental procedures

14 Rheumatoid arthritis cervical spine MRI

15 Rheumatoid arthritis extra-articular symptoms Rheumatoid nodule Pericarditis Pulmonary fibrosis Rheumatoid vasculitis Secondary Sjögren s syndrome, episcleritis, scleritis, scleromalacia perforans Nervous system involvement compression neuropathy (tunnel syndromes) polyneuropathy / multiple mononeuritis craniocervical instability Secondary amyloidosis Accelerated atherosclerosis Osteoporosis Lymphoma

16 Rheumatoid nodule Subcutaneous nodules on the extensor surfaces of the limbs Their presence is usually associated with a more severe disease course. Rarely they may be found in the heart and lung too.

17 Rheumatoid vasculitis Requires high dose intravenous corticosteroid and cyclophosphamide treatment

18 Episcleritis, scleritis, scleromalacia perforans

19 Arthritis and atherosclerosis Lot of common mediators - CRP, autoantibodies, lipids, adhaesion molecules

20 CV event-free probability Untreated RA carries the same cardiovascular risk as type-2 diabetes mellitus Control T2DM RA years

21 CVD is the most prevalent extra-articular and systemic manifestation in RA Prevalence of ExRA and SysM by year Year Hochberg MC et al. Current Medical Research and Opinion 2008; 24(2):

22 Rheumatoid arthritis pathogenesis I. Genetics Polygenic (more than 50 risk loci identified -Most of the risk is carried by HLA-DR4 alleles, that share a common antigen-binding motif ( shared epitope ) Environmental factors -Smoking -High fat diet -Excessive caffeine -Alcohol protective (in moderate amounts)

23 The role of citrullinated peptides in RA Arginine Citrulline Post-translational modification by PAD (peptidil-arginin deiminase) A biochemical pathway universally present in inflammatory processes Result: citrullinated vimentin, fibronectin, EBNA, fibrin If particular, special citrullinated epitopes are formed these may behave as autoantigens Shared epitope (serologically: HLA-DR4, by genotyping: HLA DRB1*0401, 0404, 0408 ) short, structurally similar sequences located on the 3rd hypervariable region of the HLA-DRB1 chain, which bind similar peptide sequences on various proteins and present them as (auto)antigens

Histograms of odds ratios for developing anti-ccp-positive (A) and anti-ccp-negative (B) rheumatoid arthritis (RA) for different combinations of absence or presence of single or double HLA- DRB1

24 Histograms of odds ratios for developing anti-ccp-positive (A) and anti-ccp-negative (B) rheumatoid arthritis (RA) for different combinations of absence or presence of single or double HLA- DRB1 shared epitope (SE) alleles, and smoking Risk of development of RA: smoking: 3x, shared-epitope (double gene copies): 5x, smoking + shared-epitope: 25x synergistic geneticenvironmental interaction Kallberg et al Am J Hum Genet 2007;80:867 75)

25 Periodontitis and RA are closely associated Source:

26 Association between periodontal disease and RA Hyppocrates: pulling teeth may cure arthritis Periodontal disease is more prevalent among smokers Periodontitis is more common in RA patients Rutger Persson G, J Oral Microbiol 2012, Bertehlot JM, Joint Bone Spine 2010 Smoking is a shared risk factor the association is present also in non-smokers Potikuri D, Ann Rheum Dis 2012

27 Association between periodontal disease and RA The severity of periodontal disease correlates with disease activity of RA Kobayashi T, J Periodontol 2010 Antibiotic or dental treatment of periodontitis reduces RA disease activity Ortiz P, J Periodontol 2009 Severe periodontal disease diminishes the therapeutic efficacy of anti-tnf therapy of RA Savioli C, J Clin Rheum 2012 Anti-TNF therapy may improve periodontitis Mayer Y, J Periodontol 2009 Alveolar bone loss is parallel with juxtaarticular bony erosions of RA patients 2006 Marotte H, Ann Rheum Dis

28 Porphyromonas gingivalis a major player in the switch from periodontitis to RA? Anaerobic rod-shaped bacterium Rarely present in periodontally healthy individuals Its colonization in the periodontal sac is necessary for the development of periodontitis Unique among prokaryotes for expressing PAD

29 Summary current concept of RA pathogenesis Smoking: chronic inflammation in periodontal tissues and bronchi pro-immunogenic milieu altered microbiome increased citrullination In HLA-DR4 shared-epitope carriers: citrullinated epitopes generate anticitrullinated peptide antibodies A subsequent further hit : these antibodies become pathogenic and cause arthritis

30 Rheumatoid arthritis pathogenesis what happens in the synovium? Key players potential drug targets

31 Rheumatoid arthritis 2010 ACR-EULAR classification criteria A. Articular involvement 1 large joint large joints small joints small joints 3 >10 joints (at least1 small joint) 5 B. Serology (at least 1 positive is needed) Negative RF and ACPA 0 Low positive RF or ACPA 2 High positive RF or ACPA 3 C. Acute phase response (at least 1 positive is needed) Normal CRP and normal ESR 0 6/10 is required Abnormal CRP or ESR 1 for definite RA D. Duration of symptoms <6 weeks 0 >6 weeks 1

32 Rheumatoid arthritis - progression Irreversible damage (erosions on X- ray) appears as early as 4-6 months Delayed therapy can not eliminate subsequent destruction, it can only slow it down

33 Rheumatoid arthritis principles of therapy Early diagnosis Early recognition (effective therapy has to be initiated not later than 3 months after the first symptoms!) Differential diagnosis must be thorough but rapid Bad prognostic signs Anti-citrullinated peptide antibody-positivity Early erosions on X-ray High number of inflamed joints Early initiation of immunosuppressive treatment T2T = treat to target: goal: complete remission (=no inflamed joint, normal C-reactive protein). If suboptimal therapy: joint damage will continue to progress

34 The concept of early arthritis Joint pain and swelling not due to trauma or infection The involvement of at least 2 articular regions MCP or MTP involvement At least 30 minutes of morning joint stiffness These patients have RA or are at high risk of RA: therefore, after thorough but rapid differentialdiagnosis (exclude infection, malignancy, SLE, etc.), initiation of a DMARD (disease-modifying antirheumatic drug) treatment is indicated, ideally within six weeks

35 Rheumatoid arthritis treatment I. Anti-inflammatory treatment non-steroidal anti-inflammatory drug (NSAID) rarely enough corticosteroid ( ~ 8-24 mg methylprednisolon/day) first 3 months of therapy, then taper off! DMARD (disease-modifying anti-rheumatic drug) slow action, inhibition of progression the induction of long-lasting remission in early arthritis? methotrexate Leflunomide hydroxychloroquin sulfasalazine

36 Rheumatoid arthritis treatment II. Disease-modifying anti-rheumatic drugs (DMARD) Interfere with the basic processes of disease pathogenesis not symptomatic therapies Action takes effect 2-3 months after the initiation Usually administered for many years (even decades) because the disease recurs if the drugs are stopped Immunosuppressives constant awareness for infections Liver, kidney function and blood count has to be checked every 2 months (after initiation: every 2 weeks!) Methotrexate and leflunomide are the two most potent but even these agents can induce remission only in 60-70% of patients If insufficient switch or combine In therapy resistance (disease remains active): biological or other targeted therapies should be started

37 Rheumatoid arthritis treatment III. Targeted therapies: specifically target key players of the pathogenesis (not empirical but hypothesis-driven, evidence-based therapies) Most of them are monoclonal antibodies (biological therapies) More recently, orally available, small molecular targeted therapies have been introduced (e.g. Janus kinase inhibitors)

38 RA biological therapy B-lymphocyte CD20 CD80 CTLA4 CD28 Th0 lymphocyte Plasma cell TNF- IL-1 Anti-TNF:infliximab, adalimumab, etanercept, certolizumab, golimumab IL1-receptor antagonist: anakinra CTLA4Ig (costimulation blocker): abatacept Anti-CD20 (B-lymphocyte depleting): rituximab Anti-IL6-receptor: tocilizumab Activated Th1 lymphocyte IL-6 Synovial cell / macrophage

40 Biological therapy in rheumatology RA: anti-tnf, B-cell depletion, IL6-inhibition, costimulation-blocade Ankylosing spondylitis, psoriatic arthritis anti-tnf, anti- IL17 Juvenile idiopathiic arthritis polyarticular form anti-tnf Juvenile idiopathic arthritis systemic form IL6-blocker, IL1-blocker Systemic lupus erythematosus, ANCA-associated vasculitis (dermatomyositis, systemic sclerosis/scleroderma, Sjögren s etc.): B-cell depletion Hereditary autoinflammatory syndromes: IL1-blocker Polymyalgia rheumatica, giant cell arteritis: IL6-blocker

41 Rheumatoid arthritis: biological therapy When to use them? In persistently active polyarthritis despite methotrexate, subsequently combined DMARD (MTX + LEF, MTX + AZA, MTX + cyclosporin ) about 20% of all RA cases Forms of administration: subcutaneous injection (home administration) or iv. infusion (outpatient unit-based administration) Contraindications: active or latent tuberculosis (PPD test, Quantiferon), impaired left ventricular systolic function (EF < 50%), hepatitis B or other chronic infection, recent maligancy First line: anti-tnf, IL6-blocker Addition of methotrexate or leflunomide is recommended (or even mandatory for some biologicals) Inefficacy or adverse effects: switch other anti-tnf or other drug class. Long-standing complete remission: 30-50% Permanent cessation? Personalized biological therapy?

Patient #1. Rheumatoid Arthritis. Rheumatoid Arthritis. 45 y/o female Morning stiffness in her joints >1 hour

Patient #1. Rheumatoid Arthritis. Rheumatoid Arthritis. 45 y/o female Morning stiffness in her joints >1 hour Patient #1 Rheumatoid Arthritis Essentials For The Family Medicine Physician 45 y/o female Morning stiffness in her joints >1 hour Hands, Wrists, Knees, Ankles, Feet Polyarticular, symmetrical swelling