Rheumatoid Arthritis: New tests, new treatments and. Christine H Jones MD Assistant Professor of Medicine UVM/FAHC

Transcription

1 Rheumatoid Arthritis: New tests, new treatments and new perspectives Christine H Jones MD Assistant Professor of Medicine UVM/FAHC

2 Objectives Discuss physical and laboratory findings in rheumatoid arthritis (RA) and their significance Discuss factors influencing the prognosis of RA Review changing role of disease modifying anti-rheumatic drugs (DMARDS) in treatment of RA

3 Inflammatory arthritis Rheumatoid arthritis is the classic example of an inflammatory arthritis

4 Characteristics of Inflammatory Arthritis* Morning stiffness of >1 hour duration Improvement in symptoms with activity Pain worse at rest Multiple joints affected on both sides of the body Constitutional symptoms: fatigue, malaise Lab abnormalities (elevated ESR, CRP) X-rays may reveal boney erosions

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6 What is RA? A systemic autoimmune disease characterized by chronic joint inflammation Although articular disease is primary manifestation extra-articular manifestations are frequent these may include: Skin disease Hematologic disease Pulmonary disease Ocular disease Vascular disease

7 Why does RA still matter? Most common inflammatory arthritis, affects 1% of adults worldwide Peak onset in prime of life age but occurs as any age Responsible for 9 million doctor visits a year and 250,000 hospitalizations a year Direct annual cost approx $5.5 billion 20-30% of patients become disabled within 3 years of diagnosis

8 5-D-1: ACR 1987 classification criteria for rheumatoid arthritis

9 Limitations of ACR criteria for RA Although useful the criteria are not definitive In some cases RA becomes obvious over time even if criteria are not met. Sometimes another diagnosis reveals itself (e.g. systemic lupus, parvo virus or psoriatic arthritis) Does not include CCP antibody

10 A typical case A 40 year old woman presents with a 6 month history of pain in her joints. Her hands, wrists, and feet feel swollen and sometimes look bruised especially over the metacarpophalangeal (MCP) joints and the metatarsophalangeal (MTP) joints.

11 A typical case Her symptoms are worse at rest and improve with activity. She sleeps poorly and has been waking with pain in her wrists. She has been troubled by hand weakness and a picky sensation in both thumbs and index fingers.

12 A typical case She is very stiff in the morning. In the morning she also runs hot water over her hands to improve pain and stiffness. Ibuprofen improves stiffness and pain by 30% but wears off quickly. Her morning stiffness lasts 3 hours each day

13 Medications: Ibuprofen 600 mg tid. Allergic to Sulfa Habits: 4 cups of coffee/day. Drinks 1-2 beers/month Family History: Mother with rheumatism. A sister has hypothyroidism Social history: Married with 2 children. Teaches 2nd grade.

14 Physical Exam Highlights Skin exam is negative except for the presence of a firm, mobile, non-tender nodule over the olecranon of the right elbow.

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16 Rheumatoid Nodules Subcutaneous nodules in RA have a rubbery texture, and may be mobile or adherent to the underlying bone. They have a characteristic microscopic appearance They are found in areas exposed to pressure or trauma: Elbows, tops of finger joints. Also over tendons at the ankles and feet.

17 Musculoskeletal Exam: Hands There is fusiform swelling of digits 2-5 bilaterally. There is swelling at the MCP joints, especially the 1 st MCP. There is pain on palpation of the PIP joints. There is pain on end-rom with flexion of the PIP and MCP joints. Grip strength is decreased

18 Subtle hand swelling early in RA Pip swells MCP swelling

19 Changes in hands in long standing RA are often different than those early in the disease Note changes in MCPS Changes predominate in dominant hand (here the right hand) This can be referred to as a windswept appearance

20 Swan neck fingers.

21 Boutiniere deformity of hands

22 Netter s version of hand changes

23 Sample patient exam: Wrists Wrists appear swollen. Wrists are tender to deep palpation. There is pain and reduced ROM in both There is pain and reduced ROM in both wrists.

24 5-C-9: Rheumatoid arthritis: hands, subluxation and muscle atrophy

25 Musculoskeletal Exam Neck and low back: Non-tender with normal range of motion Shoulders: Non-tender with pain bilaterally with end-rom flexion Elbows: Non-tender with full ROM

26 Musculoskeletal Exam Hips: Non-tender with full ROM Knees: No warmth or swelling, full ROM Ankles: Appear slightly swollen with pain on deep palpation, but full ROM Mid-tarsal joints: Pain with deep palpation, normal ROM. MTP joints: All feel swollen, pain with deep palpation and end-rom (flexion)

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28 Laboratory Data WBC 5.0 HGB 10.5 Normal liver function panel Creatinine 0.8 Platelets 433 Erythrocyte sedimentation rate (ESR): 80 C reactive protein: 5.0

29 Immunologic studies Rheumatoid factor: 240 Antibodies to cyclic citrullinated peptides (CCP) elevated at 50

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31 Factor Facts 85 % of RA patients will have a positive rheumatoid factor (RF) RA patients who do not have a RF have sero- negative RA Some patients will have a negative RF at presentation but will convert to a + RF several years after diagnosis Once RF identified, serial measurements of RF titer are NOT helpful in monitoring disease

32 What are antibodies to Cyclic Citrullinated Peptides (anti-ccp ab)? Antibodies directed against antigens containing citrulline, an infrequent amino acid found in modified fibrin and present in increased levels in the rheumatoid joint. First described 30 years ago, put into clinical use 3 years ago.

33 Anti-CCP antibodies Anti-CCP antibodies have a sensitivity comparable to that of RF Sensitivity 68-70% Anti-CCP antibodies are more specific for RA than RF alone Specificity 98% Arthritis Rheum2000;43:

34 Use of Anti-CCP antibodies and RF Presence of both anti-ccp antibody and RF is associated with virtual diagnostic certainty and greater disease severity of RA

35 Imaging studies Early in the disease radiographs may be useful to evaluate for joint space narrowing, erosions and periarticular osteopenia.

36 5-R-8: Rheumatoid arthritis: hand, soft-tissue swelling (roentgenogram) Radiograph: early RA

37 Erosion of ulnar styloid

38 Radiographs and progression of disease over time Within the first year of RA radiographically apparent erosions are identified in 15-30% of patients After 3 years 70-90% of patients will have radiographically evident bone erosions and joint space narrowing. The relationship between developing joint destruction seen via X-ray and its long term consequences are unclear.

39 Newer imaging modalities Ultrasound and MRI Allow more specific assessment of the inflamed joint, detect more bone erosions earlier than X-rays. Are they worth it given the additional costs? Studies are lacking at this time.

40 MRI Can be oh so Revealing..

41 EARLY DIAGNOSIS=EARLY TREATMENT (FEAR the DISEASE NOT the DRUGS) Substantial evidence that use of disease modifying anti-rheumatic drugs (DMARDS) early in the course of treatment leads to earlier disease control and less joint damage.

42 American College of Rheumatology (ACR) RA guidelines Patients with suspected RA should see a rheumatologist within 3 months of presentation for confirmation of diagnosis and institution of treatment

43 American College of Rheumatology Initial RX : (ACR) RA guidelines Education of patient regarding disease NSAIDS for rapid pain relief Low-dose corticosteroids as a bridge therapy at initiation of slower-acting DMARD therapy

44 DMARDS: Hydroxychloroquine (Plaquenil) Effective for mild RA. Used in combination therapy for moderate to severe RA Side effects Nausea Rash Ocular toxicity (Reversible retinal deposits) Myopathy (Vacuolar)

45 DMARDS: Minocycline Recently found to be effective in treatment of mild RA Usual dose mg po qd Inhibit matrix metaloproteinase inhibitors, in synovium Side effects sun-sensitivity dizziness grayish skin discoloration with long term use

46 DMARDS: Sulfasalazine Sulfa allergy contra-indication Usual dose 1 to 2 grams BID Up to 3 months until clinical improvement Side effects Nausea- very common blood dyscrasias G-6-p dehydrogenase deficiency results in serious anemic crisis reduces male sperm count

47 DMARDS: Methotrexate The gold standard Usual dose mg po or sq 1 day a week side effects hepatic function abnormalities blood cell dyscrasias pneumonitis oral ulcers- folate may prevent nausea the blahs

48 Methotrexate and Alcohol In general patients in the US are advised to consume no alcohol while taking Methotrexate In Europe and Britain physicians advise patients to limit their consumption of alcohol to 3 units or less in a week No one knows how much alcohol is too much for patients on Methotrexate

49 Methotrexate and Liver Biopsy In 1970 s Methotrexate was first used to treat RA. Great concern regarding hepatotoxicity lead to recommendation that all patients who take >5gm of Methotrexate (life time dose) be biopsied Many biopsies were normal, currently biopsies only performed for persistently abnormal LFT s

50 DMARDS: Methotrexate Recent study: Drinking 5 or more cups of coffee may reduce efficacy of methotrexate Arthritis Rheum Feb;48(2):571-2

51 DMARDS: Leflunomide (Arava) Novel pyrimidine inhibitor Efficacy similar to methotrexate Usual dose 20mg/day orally. Side Effects alopecia diarrhea abnormal LFT s rash

52 FDA Review: Leflunomide and hepatotoxicity Postmarketing reports showed a surprising increase in hepatotoxicity 29 cases of hepatotoxicity, confounded by other possible causes. Bottom line: Safe when LFTs monitored The FDA is still watching closely Am J Med Sci Apr;323(4):190-3.

53 Biologic DMARDS: TNFα Inhibitors New to scene in late 1990 s Infliximab Etanercept Adalimimab New in the last several years Golimumab Certroluzimab

54 TNFα Inhibitors general comments Studies suggest that all work best in combination with methotrexate. Combining therapy with methotrexate often leads to lower dose of methotrexate and better disease control with less toxicity Trend towards early use of combination TNFα and methotrexate therapy. Cost sometimes prohibitive

55 Using TNFα Blockers: Caveats If bacterial or serious viral infection occurs hold drug. Higher incidence of serious infections in DM May activate hepatitis B in patients with chronic infection Patients need PPD prior to starting therapy if + and no prior RX: 6 months of INH & B6 or an ID consult

56 DMARDS: Infliximab (Remicade ) Chimeric Antibody directed against TNFα ¾ human and ¼ mouse Binds TNFα in solution or attached to cell Used with Methotrexate, given IV Side effects Anaphylaxis (rare) Risk of infection- bacterial Pancytopenia Can exacerbate CHF. (Avoid in class 3 or 4)

57 DMARDS: Etanercept (Enbrel ) Soluble Receptor for TNF Given 25mg/sq two days a week Mono or combination therapy Side effects Injection site reaction Pancytopenia? safety in MS-may exacerbate or provoke disease Some patients develop + ANA

58 DMARDS: Adalimimab (Humira ) Approved 12/31/02 Soluble TNF blockade Derived from human IgG Usual dose: 40mg sq 2 times a month Side effects Increased risk infection Injection site reaction (rare) Similar to etanercept

59 Do these drugs increase risk of lymphoma? FDA Report: All three anti TNF drugs associated with higher than expected rate of lymphoma, however, cases resemble the pattern of lymphomas seen in RA. Increased in lymphoma confounded by use of Methotrexate and other DMARDS Bottom Line: Increased lymphoma risk appears to be tied to RA rather than a particular drug.

60 Black Box Warnings In 2008 FDA released a Black Box Warning Regarding the incresed Regarding the incresed risk of activation of latent TB and risk of infection especially TB with TNFalpha inhibitors ENBREL and HUMIRA

61 BLACK BOX WARNING World wide 200,000 cases of TB occurring in patients on ENBREL Enbrel was FDA approved in 1998, infliximab shortly after. Humira has been available since % of Enbrel patients have developed TB, usually miliary since it came in to use. (rate is 0.007% in US and Canada)

62 Newer drugs: Orencia (abatacept) Given IV every 4 weeks Can also increase risk of activation of latent TB Also data to suggest patients with COPD may be at risk for lung cancer (controversial) Used for patients who fail TNF α inhibitors

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64 Newer drugs: Rituxan (rituximab) Given IV with concomitant methotrexate therapy. Two infusions two weeks apart. Every 6-8 months Reserved as second-line biological therapy. i.e. Used after oral and TNF α therapy has failed

65 Caveats: Rituximab Increased risk of activation of latent hepatitis. Especially Hepatitis B Some cases of severe liver failure and death described Increased risk and activation of latent TB Risk of anaphylaxis, PML and probably any type of infection (later less clear thus far)

66 Where will the money come from to pay for these new drugs? The test of our progress is not whether we add more to the abundance of those who have too much; it is whether we provide enough for those who have too little. Franklin Delano Roosevelt, Second Inaugural Address, 1937

67 Points to ponder 1 3% of women may develop rheumatoid arthritis is their lifetime. The disease most often begins between the The disease most often begins between the fourth and sixth decades of life; however, RA can develop at any age.

68 Put another way.

69 Theories and observations Among women the disease may present when estrogen levels are low. 1. Following pregnancy 2. During the peri-menopausal period 3. 95% of women with RA experience an improvement in symptoms during pregnancy- a high estrogen state

70 Prognosis of Rheumatoid Arthritis* Poor prognosis is associated with: Positive rheumatoid factor Presence of rheumatoid nodules Presence of erosions on X-ray Involvement of multiple joints Extra-articular manifestations HLA-DR4 genotype Being a man Young age at onset Smoking

71 What are extra-articular manifestations of RA? Signs of the disease that do not involve the joints. Some examples: Pleural effusions Rheumatoid nodules Eye disease (scleritis) Rheumatoid Vasculitis Felty s syndrome

72 Summary Rheumatoid arthritis is a chronic disease but is highly treatable. Early diagnosis and treatment are key to preventing future disability Older drugs combined with new drugs provide effective therapy for many but not all patients with RA

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