New Onset Arthritis. Clinical Dilemmas in Arthritis and Rheumatology. Physical Examination. Other Pertinent History

Transcription

1 New Onset Arthritis Clinical Dilemmas in Arthritis and Rheumatology Primary Care Principles and Practice October 2008 Jonathan Graf, MD Assistant Professor of Medicine, UCSF Division of Rheumatology, SFGH 34 year old female presents to your office complaining of 6-7 weeks of low grade fevers, fatigue, flu like symptoms, and pain in her hands, wrists, feet and right knee. There is morning stiffness in her hands that lasts for about an hour and is relieved with activity. Over the counter naproxen relieves some but not all of her symptoms. Other Pertinent History Past medical history: hepatitis C Family history: mother with hypothyroidism Social history: ½ PPD smoking for 15 years Medications: Naproxen prn Physical Examination Well appearing young female No rashes, oral ulcers, alopecia Normal chest and cardiovascular exam Musculo-skeletal: synovial swelling and tenderness in her wrists, MCPs, PIPs. + pain with squeezing of MTPs. + Warm right knee with small effusion 1

2 Laboratory Tests CBC: Mild thrombocytosis Chem panel: WNL LFTs: Mild elevation of ALT only ANA + 1:80 (normal less than 40) RF (normal less than 20) Anti-CCP antibodies: +35 (normal <20) ESR: 56 (normal <20) hscrp: 14.7 (normal <0.3) HCV +, HBSag neg Radiographs Subtle soft tissue swelling MCPs and PIPs Periarticular osteopenia No significant joint space narrowing, erosions, or deformities Question #1 Which of the following statements regarding this patient is correct? A. This patient has hepatitis C associated arthritis B. This patient has Rheumatoid Arthritis C. This patient has arthritis associated with lupus because her ANA is positive D. The patient s diagnosis is unclear at this point because it is too early to differentiate her arthritis from a viral/parvoviral arthritis Question #1 Which of the following statements regarding this patient is correct? A. This patient has hepatitis C associated arthritis B. This patient has Rheumatoid Arthritis C. This patient has arthritis associated with lupus because her ANA is positive D. The patient s diagnosis is unclear at this point because it is too early to differentiate her arthritis from a viral/parvoviral arthritis 2

3 Why this patient likely has RA A. This patient does not have hepatitis C associated arthritis Hepatitis C infection is associated with a polyarticular arthropathy Generally athralgias > frank inflammatory arthritis (if inflammation present, usually mild) Rheumatoid Factor is non specific for RA. Majority of HCV patients are RF+ and usually high titer Usually non-erosive arthropathy Why this patient likely has RA C. This patient does not have arthritis associated with lupus because her ANA is positive ANA is non specific for Lupus and can be seen in RA & other CVD Lack of other clinical features of SLE Presence of thrombocytosis rather than thrombocytopenia This patient has EARLY RA D. It is not too early to differentiate her arthritis from a viral/parvoviral arthritis - The diagnosis of RA can be tricky - ACR criteria for RA stress that arthritis symptoms be present for >=6 weeks - Helps differentiate from viral arthritis - Symptoms frequently insidious in onset - Up to 50% can be RF negative at presentation ACR Criteria for the Classification of Rheumatoid Arthritis (>4 criteria required; 1-4 must be present > 6 wks) Morning stiffness > 1 hr Arthritis of 3 or more joint areas Arthritis of wrists, MCPs, and/or PIPs Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes 3

4 Limitations of ACR Classification Criteria for the diagnosis of early RA Developed for the classification of patients with longstanding disease For early RA: Specificity: 90% Limited sensitivity: 40-65% Diagnosis of early RA by ACR criteria van Gaalen et al Arth Rheum 50: 709, patients with early inflammatory arthritis Initial evaluation After 3 years 205 RA by ACR criteria undifferentiated 127 RA arthritis 413 other diagnoses RA: classic presentation Female in third or fourth decade of life Insidious onset Persistent Inflammatory polyarthritis AM stiffness (hours) Symmetric Hand involvement Rheumatoid factor Question II Which of her following clinical features is most specific for her diagnosis of Rheumatoid Arthritis? A. Her positive anti-ccp antibodies (35: normal<20) B. Her high titer RF titer (1:2560: normal <20) C: Her hscrp is elevated (14.7: normal <0.3) D. The presence of synovitis on exam 4

5 Question II Which of her following clinical features is most specific for her diagnosis of Rheumatoid Arthritis? A. Her positive anti-ccp antibodies (35: normal<20) B. Her high titer RF titer (1:2560: normal <20) C: Her hscrp is elevated (14.7: normal <0.3) D. The presence of synovitis on exam Question II: Other Answers RF is non specific and highly associated with hepatitis C hscrp is non specific marker of inflammation Many causes of inflammatory arthritis can cause elevated hscrp Synovitis can be seen in many CVD, viral arthritis, etc Our Patient with Early RA: Sensitivity and Specificity Problem Sensitivity: ACR criteria lack relative sensitivity in early RA Delay the diagnosis and initiation of therapy Specificity: RF and inflammatory markers are not specific enough in this patient with HCV Diagnosis of early RA by ACR criteria van Gaalen et al Arth Rheum 50: 709, patients with early inflammatory arthritis Initial evaluation After 3 years 205 RA by ACR criteria undifferentiated 127 RA arthritis 413 other diagnoses 5

6 Factors predictive of progression from undifferentiated arthritis to RA van Gaalen et al Arth Rheum 50: 709, 2004 At initial evaluation OR (95% CI) Positive rheumatoid factor 1.7 ( ) Positive anti-ccp antibody 38.6 ( ) Posttranslational modification of proteins: PADI converts arginine to citrulline RA-associated autoantibodies that recognize peptides containing citrulline Girbal-Neuhauser et al J Immunol 162: 585, 1999 Peptide sequence Antibody recognition Antibodies to citrullinated peptides in RA Detected by ELISAs using synthetic cyclic citrullinated peptides (CCP) ESSRDGSRHPRSHD PADI ESSRDGScitHPRSHD No Yes Sensitivity for early RA: 50% Sensitivity for later RA: 70-80% Specificity for RA: 95-98% 6

7 Anti-CCP Antibodies are Specific for RA vs. Hepatitis C Wener et al. Arthritis Rheum Jul;50(7): RF and anti-ccp testing in a cohort of 182 early RA patients Quinn et al Rheumatology (Oxford) 45:478, 2006 RF+CCP- RF-CCP- RF-CCP+ RF+CCP+ Clinical utility of the anti-ccp antibody test Diagnosis: Clinical suspicion of rheumatoid arthritis Undifferentiated inflammatory arthritis Distinguish RA from other RF + polyarthritis Not useful to monitor disease activity Best single predictor for destructive disease in patients with early onset RA Progression of joint damage in subgroups of early RA Huizinga et al Arthritis Research& Therapy 7: 949, 2005 radiographic joint damage score anti-ccp + anti-ccp - 7

8 Question III The next best step in this patient s management would be A. To start an NSAID and advance to a DMARD in 2-3 months if not adequately controlled B. To start methotrexate immediately C. To check her hepatitis C viral load, and if less than 10 4 copies/ml, then start methotrexate D. None of the above Question III The next best step in this patient s management would be A. To start an NSAID and advance to a DMARD in 2-3 months if not adequately controlled B. To start methotrexate immediately C. To check her hepatitis C viral load, and if less than 10 4 copies/ml, then start methotrexate D. None of the above Points specific to Question III This is obviously a challenging case RA: Chronic Joint Destruction and Disability What We Try to Prevent 1. NSAIDs are no longer the standard of care for first line therapy of RA a DMARD is 2. Hepatitis C is a contraindication to use of methotrexate. 3. If MTX absolutely must be used, done in conjunction with liver biopsy: Hep C viral load of no utility 8

9 Early RA: The Window of Opportunity to Intervene Joint damage in RA: progressive narrowing and erosion of a MCP joint At presentation: 1 year 5 years normal Irreversible damage can develop within months of onset of RA 1 year prior to 6 months after 3 years after onset onset of RA onset of symptoms of symptoms Radiographic changes in the same joint over time The Window of Opportunity Eventually Closes for Many. Chronic disease progression leads to permanent joint deformity, destruction, and disability Empirically, RA is a different disease the longer disease activity progresses without effective control More difficult to suppress activity and treat More extra-articular disease? 9

10 Treatment of early RA Effective treatment should be started when the diagnosis is made Effective treatment = therapies shown to slow joint destruction Goal is to induce and then maintain remission Combination of drugs more effective than monotherapy Ra: Traditional Treatment Paradigm Pyramid of therapy Start conservatively Gradually ascend the pyramid in order of potency and toxicity of therapy Only the most severely affected patients receive immuno-supressive, DMARDs DMARD therapy begun only after period of significant delay Re-Thinking the RA Treatment Pyramid Emphasizes earlier diagnosis and initiation of therapy with disease modifying anti-rheumatic drugs ACR RA Practice Guidelines 2002 Most patients with Rheumatoid Arthritis should be evaluated expeditiously Treatment with DMARD instituted within 3 months of diagnosis Goals are to prevent or control joint damage, prevent loss of function, and decrease pain 10

11 DMARD Therapies Methotrexate Leflunomide (Arava) Sulfasalazine Azathioprine Mycophenolate Mofetil Corticosteroids Hydroxychloroquine Minocycline Combination DMARD Therapies: Some Step Up Methotrexate Prednisone +/- Sulfasalazine +/- Plaquenil Methotrexate X Lefl. Generally not done Combination DMARD Therapies: Others Step Down Combination DMARD Therapies: Others Step Down Methotrexate +SSZ +Plaquenil +/- Prednisone Methotrexate +SSZ +Plaquenil 11

12 Combination DMARD Therapies: Others Step Down Why Move Towards Combination Regimens with Biologics?? Methotrexate For many RA patients, DMARDs alone effectively control symptoms For others not contolled, addition/combination of anti TNF biologic therapy is being instituted earlier The Current Pyramid Paradigm DMARD Options for our Patient Methotrexate Leflunomide (Arava) Sulfasalazine Low dose corticosteroids Azathioprine Minocycline Early initiation and titration of DMARD If incomplete response to DMARD alone, after reasonable titration, addition of biologic recommended 12

13 Is there anything else to offer this patient: Biologic Therapies?? Anti-Tnf medications Etanercept (cytokine receptor fusion protein) Infliximab (anti-cytokine antibody) Adalimumab (anti-cytokine antibody) B-cell depleting agents (monoclonal antibody) Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra Is there anything else to offer this patient: Biologic Therapies?? Anti-Tnf medications Etanercept (cytokine receptor fusion protein) Infliximab (anti-cytokine antibody) Adalimumab (anti-cytokine antibody) B-cell depleting agents (monoclonal antibody) Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra Anti TNF Therapy & Hepatitis C TNF appears to be implicated in chronic liver injury rather than having protective anti-viral effects Some clinical evidence to support benefit in HCV cirrhosis Interval monitoring of LFTs recommended Summary of Observational Studies in RA with Hepatitis C: Study Year n Mean f/u (months) Peterson et al Park and Reveille Ferri et al Earlier studies: etanercept and infliximab. More recent include some patients on Adalimumab All studies show no increase in transaminases or viral load 1. Ann Rheum Dis Nov;62(11): Arthritis Rheum Oct 15;51(5): J Rheumatol Oct;35(10):

14 This is a Challenging Case of Early Rheumatoid Arthritis Timely recognition is challenging Hepatitis C arthritis can mimic RA (especially mild RA) and confound specificity of diagnosis Hepatitis C is highly associated with RF+ which also confounds diagnosis Using ACR criteria alone will miss many patients with early RA Prompt treatment with DMARD therapy is absolutely essential to prevent long term complications Hepatitis C status complicates therapeutic choices Early RA Dilemmas: Summary RA can be difficult to diagnose early in its course Problematic because early DMARD treatment is essential for long term benefits Anti-CCP antibody assay very beneficial in differentiating RA from other causes of inflammatory arthritis and Hep C arthritis Needs to be used in right clinical context for maximum positive predictive value Negative predictive value lower, especially in early RA Prognostic potential if anti-ccp + Difficult RA Dilemmas: Summary Early initiation of DMARD essential Hep C + precludes use of most DMARDs that are potentially hepatotoxic: eg. MTX Hepatitis antibody status usually checked before initiating methotrexate, leflunomide, etc. Also counsel about birth control and ETOH abstinence Sulfasalazine appropriate DMARD to start, but might not be strong enough Use of anti-tnf therapy in RA patients with Hep C is now being tried, although further long term studies needed La Cortisone: Raul Dufy 14

15 Case II: A Chest Full of Questions 46 year old female diagnosed 14 years ago with SLE when she presented with proteinuria, skin rashes, oral ulcers, and a polyarticular arthrtitis in her hands. ANA +, anti-dsdna+, and anti-smith +. Initially treated with prednisone, hydroxychloroquine, and azathioprine with success. Case II continued Intermittently, she d report flares of fatigue, pleuritic chest pains, oral ulcers, arthritis and rashes a few times/year, treated by her medication and corticosteroid dosages. Over the past 4 months, she notes episodes of dyspnea on exertion, intermittent chest pain, especially when she s breathing heavily, and fatigue. Case II, continued Past medical history is as described Habbits: smokes ½ PPD X 20 years, occasional ETOH, no illicit drug use Medications: methotrexate (for past 6 months), prednisone, & hydroxychloroquine 15

16 Case II, physical exam HEENT: malar erythema, no oral ulcerations Chest: slight dullness at left lung base but lung fields are generally clear CV: regular rate, rhythm, +s4, no murmurs, no audible rubs ABD: NT/ND without hepatosplenomegaly EXT: No edema Skin: No other rashes Musculokeletal: no synovitis Subacute Chest Pain and SLE The least useful test in working up this patient s symptoms is which of the following: A. CXR B. EKG, cardiac stress testing C. Anti-ds DNA Ab. Titer D. Echocardiogram E. CT angiography Subacute Chest Pain and SLE The least useful test in working up this patient s symptoms is which of the following: A. CXR B. EKG, cardiac stress testing C. Anti-ds DNA Ab. Titer D. Echocardiogram E. CT angiography Etiologies of Chest pain in SLE Pleuritis: Exudative pleural effusion Pneumonia: SLE patients are doubly susceptible to infectious complications from SLE, itself from the use of immunosupressive therapies 16

17 Other pulmonary complications Methotrexate hypersensitivity (top right) Fever, cough, SOB, flu Interstitial infiltrates and fibrosis Lupus associated acute pneumonitis (rare) Chronic ILD Boop, UIP, NSIP Diffuse alveolar hemorrhage Shrinking lung syndrome (bottom right) Pericarditis and SLE Most common cardiac manifestation 18% in Hopkins SLE cohort Exudative Usually occurs early in course of disease Frequently co-exists with pleurisy Frequently sub clinical Can rarely cause tamponade <1% Hopkins SLE cohort Pulmonary Embolus SLE patients can be hypercoagulable Antiphospholipid antibodies Nephrotic syndrome Anti-dsDNA Antibodies Highly specific for SLE: 90-95% Not very sensitive: 50% In some but not all patients, titers correlate with disease activity, especially renal If titers are negative or unchanged, does not mean that SLE is not active Likewise, if the titers are elevated, does not mean that this patient s chest pain is due to ACTIVE SLE 17

18 SLE: The Seriousness of Chest Pain Infectious complications were classically thought of as leading cause of mortality Growing evidence that ischemic heart disease now leading cause of mortality Risk of CV disease in SLE patients is 7-50 fold greater (dwarfs diabetes and cholesterol and other traditional CV risk factors!!) Cardiac symptoms should be treated seriously in all SLE patients, including young women, and on all board exams!!!! Myocardial Ischemia and SLE: Acute Setting All SLE patients other than those one is CERTAIN do not have CAD, should be evaluated for myocardial ischemia, including obtaining EKG and further workup Hospital setting: telemetry, troponin levels, and appropriate therapy until diagnosis secured Usually not from coronary vasculitis, or other acute SLE activity - but rather from accelerated atherosclerosis in the setting of chronic inflammation Therefore, myocardial ischemia often does not correlate with other SLE activity Chronic Management of CV risk factors Aggressive BP control <130/80 if possible Aggressive cholesterol reduction (LDL<100) Modification of other cardiac risk factors (smoking, exercise, etc ) and use of ASA SLE Chest Pain/SOB Summary Many etiologies of chest pain related to active SLE activity CXR, Chest CT (r/o PE), Echocardiogram, EKG all beneficial in evaluating such a patient depending upon clinical circumstances Keep in mind infectious complications of SLE and therapy that can cause chest pain and/or dyspnea Always treat chest pain in a long standing SLE patient as if it were cardiac ischemia until proven otherwise 18

19 Systemic Lupus Erythematosus Systemic Disorder, involving multiple organs in multiple ways Women:Men = 9:1 African American/Caribbean in US/UK: Dz. is 3 times more common Peak Age of Onset 20 s & 30 s Incidence has tripled since 1970 s to 5.56/100,000 population SLE: ACR Criteria: 4 of 11 Criteria without better explanation (Not diagnostic) Malar Rash Discoid Rash Photosensitivity Oral Ulcers Arthritis Serositis Renal Disorder 19

20 SLE Criteria Cont. Hematologic Disorder Immunologic Disorder ANA Neurologic Disorder Fixed malar distribution of erythema, flat or raised Malar Rash Discoid Rash DLE - Old Erythematous raised patches with keratotic scaling and follicular plugging; some atrophic scarring in chronic lesions 20

21 Photosensitivity Oral Ulcers Skin rash as an unusual reaction sunlight, by patient history or physical examination Oral or nasopharyngeal ulcers, usually painless, observed by a physician Arthritis Other SLE Criteria Non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion Serositis Pleuritis (convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion Pericarditis (documented by EKG, rub, or evidence of pericardial effusion) Renal Disorder Persistent proteinuria >0.5g/day (or>3+) Cellular casts of any type 21

22 Hematologic Abnormalities Hemolytic anemia (usually coomb s positive) Leukopenia (WBC < 4,000 on at least 2 occasions) Lymphopenia (<1500 on 2 or more occasions) Thrombocytopenia (PLT<100,000 on 2 or more occasions) Immunologic Disorder One of the Following Anti-dsDNA Anti-Smith Positive findings of anti-phospholipid Abs Abnormal level of either IgG or IgM CLIP Abs Positive test for Lupus Anticoagulant (RVVT) False positive RPR/VDRL > 6months neg. FTA Positive ANA An abnormal titer of ANA in the absence of drugs known to be associated with druginduced lupus syndrome Neurologic Disorder Classically defined only as: Seizures (in the absence of other causes) Psychosis (in the absence of other causes) Other CNS manifestations Headaches Cognitive dysfunction 22

23 Organ System Involvement in Flares of SLE, Hopkins Cohort:1991 Constitutional 66% Musculo-skeletal 58% Dermatologic 47% Renal 22% Neurologic 21% Hematologic 17% Serositis 12% Pulmonary 7% Permanent Organ Damage in SLE, Hopkins Cohort: 1991 Musculo-skeletal 25.2% Neuro-psychiatric 15% Ocular 12.6% Renal 11.7% Pulmonary 10.4% Cardiovascular 10.1% GI 7.4% Skin 7.4% Peripheral Vascular 5.5% Malignancy 2.5% Premature Gonadal Failure 1.2% 23