Advances in Medical Co- Management of Patients with Rheumatic Diseases

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1 Advances in Medical Co- Management of Patients with Rheumatic Diseases Useful updates for internists who follow patients with rheumatic diseases in their practice Jeff Critchfield, M.D. Associate Professor of Medicine Jonathan Graf, M.D. Assistant Professor of Medicine, UCSF Division of Rheumatology, SFGH May-June, 2009

2 Role of Rheumatologists and Internists/PCPs Shortage of rheumatologists in US Predicted to grow even more in coming years Overburdened schedules leave little time for complete care of complex patients with rheumatic diseases Primary care issues can be overlooked More demands on rheumatologists leave less time for primary care Rheumatologists do less (and keep up less with innovations in) primary care Greater need for specialist-pcp cooperation of patients with autoimmune diseases

3 Clinical Case: SLE 28 year old female presents to your office having been diagnosed with SLE 3 years ago when she presented with malar and discoid rashes, pleurisy with effusions, oral ulcerations, alopecia, leukopenia,, and polyarticular inflammatory arthritis in her hands. She was initially treated with prednisone, anti-malarials malarials, topical corticosteroids, and NSAIDs,, all of which she has continued to take with an excellent response. Her current dose of prednisone is 5 mg/day.

4 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, no murmurs, no audible rubs ABD: NT/ND without hepatosplenomegaly EXT: No edema Skin: No other rashes Musculokeletal: : no synovitis

5 Laboratory Testing 3 Years ago Currently ANA 1:640 Speckled Anti-Sm ++ anti-dsdna WBC PLT 154, ,000 C C U/A RBC s neg neg U/A Protein neg neg

6 Question #1 In this otherwise stable SLE patient, the most likely cause of excess mortality is which of the following? A. Glomerulonephritis and renal failure B. Myocardial infarction without coronary vasculitis C. Coronary vasculitis D. Infection

7 In this otherwise stable SLE patient, the most likely cause of excess mortality is which of the following? A. Glomerulonephritis and renal failure B. Myocardial infarction without coronary vasculitis C. Coronary vasculitis D. Infection Glomerulonephritis and... 25% 25% 25% 25% Myocardial infarction wi... Coronary vasculitis Infection

8 Question #1 In this otherwise stable SLE patient, the most likely cause of excess mortality is which of the following? A. Glomerulonephritis and renal failure B. Myocardial infarction without coronary vasculitis C. Coronary vasculitis D. Infection

Mortality in SLE Bernatsky et al. Arthritis Rheum. 2006 Aug;54(8):2550-7.

9 Mortality in SLE Bernatsky et al. Arthritis Rheum Aug;54(8): Multi-center observational SLE cohort: 9,547 patients 77,000 cumulative patient years of f/u (ave.. 8 years) Leading mortality cause: CVD Highest mortality ratio: Infection (less common than CVD in general population)

10 Recent Representative Case at UCSF 27 year old Pakistani man with SLE and glomerulonephritis diagnosed within the past year Originally treated with corticosteroid and mycophenolate immunosupression (reluctantly for him) Presented later to UCSF ER complaining of malaise and vague chest discomfort

11 CV Case, Continued Initially diagnosed with URI and mild chondritis and sent home with supportive therapy Came back days later with more chest pain, somewhat but not completely atypical EKG with ST elevations in multiple but not all leads Mild Troponin elevation Admitted with presumed pericarditis: : received no thrombolytics,, anti-coagulation, anti-platelet therapy except ASA, or cardiac catheterization

12 CV Case Cont. Next day, Troponin climbed to > 15 (markedly elevated) Echocardiogram with fixed lateral wall abnormality Perfusion imaging also suggested MI with significant CAD

13 SLE: Cardiovascular Risk Infectious complications were classically thought of as leading cause of mortality Growing evidence that ischemic heart disease now competing with infections as leading cause of mortality Risk of CV disease in SLE patients is 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!!!!

14 SLE and CV Disease Chronic inflammation and disease help drive atherogenic process Many SLE patients also have higher mean number of modifiable traditional CV factors cholesterol, HTN, diabetes, obesity, smoking Evidence of increased preclinicial CAD in SLE patients vs. controls

15 Example of Preclinical CV disease: Increased Corotid Intimal Media Thickness Shoenfeld et al. Circulation 2005;112;

16 A Reminder: Infections are still a leading cause of mortality in SLE!!! SLE patients are doubly susceptible to infectious complications 1. from SLE, itself, and 2. from the use of immunosupressive therapies Infectious complications can mimic disease activity so don t t be fooled, pan-culture, low threshold for empiric antibiotic coverage

17 Cardiovascular Disease Risk in Patients with Other Rheumatic Diseases Definite increased risk: Rheumatoid Arthritis Probable increased risk Anti-phospholipid antibody syndrome Psoriasis Inflammatory bowl disease Possible increased risk Sjogren s syndrome Scleroderma Vasculitis (definitely increased risk of venous thrombosis in partients with Wegener s granulomatosis for example)

18 RA and CV disease Overwhelming evidence of excess CV mortality, morbidity, and CV events in patients with rheumatoid arthritis Many RA patients have increased traditional Framingham risk factors Most studies now show increased CV risk remains even after adjusting for traditional CV risk factors Risk appears to be correlated to levels of inflammation in the disease

19 Early RA and CV Events Increased CV events and mortality risk is seen even in patients with early disease John H et al. Best Pract Res Clin Rheumatol Feb;23(1):71-82.

20 Early RA and Preclinical CV disease RA is associated with preclinical CV disease, in some cases even early in disease course Surrogate measurements of CAD may allow for assessment of CV risk Carotid IMT, Brachial artery flow-mediated dilatation, Coronary CT calcium scores

21 Baseline CRP levels and CV death in patients with inflammatory arthritis Goodson et al. Arthritis Rheum Aug;52(8):2293-9

22 Mitigating Cardiovascular Risk in RA/SLE Abstinence from smoking and encouragment of aerobic exercise Aggressive blood pressure management (? pre-htn) Aggressive management of lipids Manage LDL, and Tchol/HDL ratio as if at highest Framingham CV risk Addressing all potential CV symptoms promptly, even in younger females (especially in patients with SLE) In future,?? following markers of inflammation (CRP, ESR) and treating with statins?? (similar to JUPITER study)

23 Question #2: Back to our original young SLE patient

24 Question #2 Toward the end of the patient s s most recent follow up visit, she mentions that she is sexually active with a new boyfriend and desires contraception. Her gynecologist counsels her not to use estrogen containing OCPs and recommends implantation of an IUD. She seeks a second opinion from you.

25 Which of the following statements A. Estrogen-OCPs are contraindicated in patients with stable SLE because they may cause disease flares B. Low dose estrogen-ocps are safe, but higher dose HRT is not for SLE patients C. IUD s, OCP s,, and progestin only contraception are equally effective and safe in SLE patients D. OCPs aren t t as much of an issue, since fertility isn t normal in SLE patients is True? Estrogen-OCPs are cont... 25% 25% 25% 25% Low dose estrogen-ocp... IUD s, OCP s, and proges... OCPs aren t as much of..

26 Question #2 Which of the following statements is True? A. Estrogen-OCPs are contraindicated in patients with stable SLE because they may cause disease flares B. Low dose estrogen-ocps are safe, but higher dose HRT is not for SLE patients C. IUD s, OCP s,, and progestin only contraception are equally effective and safe in SLE patients D. OCPs aren t t as much of an issue, since fertility isn t t normal in SLE patients

27 Buyon JP. Oral Contraceptives in Women with Systemic Lupus Erythematosus.. Ann Med Interne 1996 Oral contraceptives (OCs( OCs) ) are generally not prescribed for women with SLE due to the widely-held view that they may activate disease. This practice is based on the greater incidence of SLE in women than in men, biologic abnormalities of estrogen metabolism, murine models of lupus, several anecdotes of patients having disease flares while receiving exogenous hormones, and a single retrospective study in patients with pre-existing existing renal disease.

28 Systemic Lupus Erythematosus Source: UK National Health Service Health and Social Care Information Center All Hospitalizations in UK from with M32 Diagnostic Code

29 Nurses Health Study Sanchez Guerrero et al. Arthritis Rheum May;40(5): ,000 subjects N=99 diagnosed with SLE Relative risk for those who had taken OCPs depending upon definition of SLE

30 SELENA: Safety of Estrogen in Lupus Erythematosus National Assessment Trial Petri, Buyon et al. NEJM women enrolled at 15 sites >4 4 ACR criteria <40 years nonsmoker or <36 smoker Stable disease > 3 mon. Composite activity score used =SLEDAI Inactive or stable milder disease Ortho-Novum 7/7/7

31 Mild Patients On less than 0.5 mg/kg corticosteroids No history of thromboembolism No history of anti- phospholipid antibodies BP <145/95

32 SELENA: Results

33 Comparison of Contraceptive Methods in SLE Patients Sanchez Guerrero et al. NEJM patients randomized to IUD (T380A), progestin pill (Microlut( Microlut), or combination pill (Nordet( Nordet) Age< 40 SLEDAI <30 (Mild-Mod Mod disease) < 15 cigarettes/day if >35 yrs/old

34 Demographics: somewhat more moderate disease SLEDAI 6 vs. 3 in SELENA 20% APLA Positive vs. 0% in SELENA

35 Mean SLEDAI Lupus Activity

36 Incidence of Lupus Flares (SLEDAI change >3; Severe if >12)

37 HRT and Lupus Flare Sanchez-Guerrero A&R 2007 Buyon J. Annals of Internal Medicine 2005 SLEDAI scores followed over 24 months Cumulative probability of severe flares over 400d. * Slight risk of thrombosis detected in Sanchez-Guerrero study * Slight increased incidence of minor flare detected in Buyon study

38 SLE & Contraceptives: Summary Oral contraceptives are safe in patients with stable or mildly active disease Different OCP methods appear equally safe Unclear, but generally not used for patients with hypercoagulability or severely active, uncontrolled disease HRT (for those still using it) is probably safe for stable-mild SLE

39 Question #3 The patient presents to your office complaining of fatigue and weight gain. You discover her to be hypertensive with an an elevated creatinine of 2.1 and an active urine sediment; renal biopsy confirms the diagnosis of rapidly progressive glomeronephritis.. Her rheumatologist wants to initiate therapy with IV cyclophosphamide and solumederol immediately. However, she is informed that premature ovarian failure is a side effect, and she seeks your advice about what to do.

40 Which of the following recommendations is not correct? A. Her risk of infertility rises with age, especially over the age of 30 B. Her risk of infertility is related to the cumulative dose of cyclophosphamide C. Her best option is to undergo egg harvest for unfertilized cryopreservation D. She should strongly consider chemical induction of anovulation Her risk of infertility rises... 25% 25% 25% 25% Her risk of infertility is rel... Her best option is to un... She should strongly co...

41 Question #3 Which of the following recommendations is not correct? A. Her risk of infertility rises with age, especially over the age of 30 B. Her risk of infertility is related to the cumulative dose of cyclophosphamide C. Her best option is to undergo egg harvest for unfertilized cryopreservation D. She should strongly consider chemical induction of anovulation

43 Answers to Question #3 A&B. Incidence of P.O.F. rises with age and cumulative cyclophosphamide dose Boumpas et al. Ann of Int Medicine 1993 Ioannidis et al. J Rheum 2002

44 Answers to Question #3 Harvesting and cryopreservation of eggs is controversial Usually requires high doses of hormonal stimulation that might be dangerous Usually requires delay in initiation of therapy (time=nephrons nephrons) Not fully proven, reliable technique

Use of GNRH Analog Protects against Premature Ovarian Failure Somers et al. Arthritis & Rheumatism 2005 40 patients randomized before receiving Iv Cyc Lupron vs.

45 Use of GNRH Analog Protects against Premature Ovarian Failure Somers et al. Arthritis & Rheumatism patients randomized before receiving Iv Cyc Lupron vs. no treatment 10 d. prior to receiving boluses Ovarian function: normal menses or fertility after protocol POF = amenorrhea > 12 months and FSH > year follow up ( )

46 Protective Effect of Lupron 1/20 (5%) of patients receiving lupron developed POF Compared to 6/20 (30%) controls 1 patient in GNRH group was in 75 th percentile of age and 99 th percentile cumulative Cyc dose OR 0.09, P<0.05

47 Lupron to preserve fertility in women receiving chemotherapy for cancer: evidence growing but limited to small trials

48 Question #4 Swine Flu is running rampant over the Western Hemisphere. The CDC announces the availability of a new H1N1 vaccine similar in composition to traditional influenza vaccines and is recommending immunization for everyone. You are currently seeing your patient with SLE and are ready to vaccinate her when you pause: You seem to remember that vaccinating patients with lupus is controversial.

49 Theoretical Risks Related to Vaccination and Autoimmunity Risk of causing disease to flare Vaccinations contain adjuvant in addition to the immunizing antigen Adjuvant stimulates the immune system to mount a protective response to the vaccine Adjuvant and the antigen may both cause autoimmunity to flare in susceptible patients Anecdotal reports of SLE onset after vaccinations

50 Other Theoretical Issues Related to Vaccination and Autoimmunity Increased Risk of Vaccination in immunocompromised patient Most therapies for autoimmune disease (DMARDs( DMARDs, corticosteroids, and cytotoxics) ) suppress immunity Certain autoimmune diseases (SLE) are immunosuppressing even without therapy Live, attenuated vaccines might not be as safe for people with suppressed immunity Diminished efficacy of vaccines in immunocompromised individuals Can they even mount a protective immune response?

51 Question #4 Vaccination with this new swine flu vaccine should be avoided in which of the following: A. All patients with SLE B. Patients with SLE who are on immunosupressive therapy C. Patients with SLE who are NOT on immunosupressive therapy D. None the above

52 Vaccination with this new swine flu vaccine should be avoided in which of the following: A. All patients with SLE B. Patients with SLE who are on immunosupressive therapy C. Patients with SLE who are NOT on immunosupressive therapy D. None the above All patients with SLE 25% 25% 25% 25% Patients with SLE who... Patients with SLE who... None the above

53 Question #4 Vaccination with this new swine flu vaccine should be avoided in which of the following: A. All patients with SLE B. Patients with SLE who are on immunosupressive therapy C. Patients with SLE who are NOT on immunosupressive therapy D. None the above

54 Influenza Vaccinations in SLE: Data Complied from Conti et al. Autoimmunity Reviews 2008

55 Question #5 Which of the following other vaccines, if not already received, would definitively be recommended for your patient at this time? A. Pneumococcal B. Hepatitis B C. Herpes Zoster Vaccine D. A&B E. None of the Above

56 Question #5 Which of the following other vaccines, if not already received, would definitively be recommended for your patient at this time? A. Pneumococcal B. Hepatitis B C. Herpes Zoster Vaccine D. A&B E. None of the Above

57 SLE and Vaccinations Vaccination with influenza vaccine does not increase SLE flares and is sero-protective in most SLE patients Although some patients on significant immunosuppressive therapy more likely not to seroconvert to vaccines Similar data for pneumococcal vaccine as for influenza. Benefits of these vaccines far exceed risks Live vaccines (eg( eg.. Zoster) are generally not given to SLE patients, especially those on therapy, although evidence for this is lacking

58 Vaccinating Rheumatoid Arthritis Patients who are on Immunosuppressive Therapy: American College of Rheumatology Guidelines for Use of Medications in Rheumatoid Arthritis Saag et al. Arthritis Rheum Jun 15;59(6):

59 Herpes Zoster Risk Affects 1 million Americans annually Increased incidence with age (esp. >60) Increased incidence with immunosuppression from disease (eg( eg.. SLE) Increased incidence with immunosuppressing medications Increased incidence of dissemination in immuno- compromised patients Theoretical benefit to immunizing patients to zoster who have autoimmune diseases

60 Live Vaccinations in RA Patients: Current Standards Existing guidelines warn against use of zoster vaccine in patients on immuno-supressive therapy No clinical trial evidence that supports this practice New CDC (Advisory( Committee on Immunization Practices) ractices) recommends Immunization with Zoster Vaccine OK in patients on low dose methotrexate,, prednisone, or imuran Should not be used in patients on biologic therapy Based on expert opinion, not on study or safety data

American College of Rheumatology Hotline: August 2008 RA and its therapy put patients at risk for Zoster and poor outcomes Weigh the risks-benefits and consider immunizing RA

61 American College of Rheumatology Hotline: August 2008 RA and its therapy put patients at risk for Zoster and poor outcomes Weigh the risks-benefits and consider immunizing RA patients, even those on methotrexate and prednisone Avoid giving to patients receiving biologic therapies (including anti- TNF) (Not peer-reviewed/published!) reviewed/published!)

62 RA: Other Vaccination Points Immunization with live, attenuated Flu-Mist Vaccine is CONTRAINDICATED Patients on immunosupression Close contacts of those patients (herd immunity) Immunization with Zoster vaccine Should not be considered for patients on anti-tnf therapy Should be strongly considered for patients prior to biologic therapy At least 2 weeks before initiation of anti-tnf therapy

63 A Difficult Case Involving a Common Disease You are seeing a 56 year old male with long standing diabetes, hypertension, chronic renal insufficiency, and destructive tophaceous gout. His gout originally began as episodic podagra that became more frequent and involved more joints over time. In the past few years, his tophi have grown larger and more numerous, and acute episodes of inflammatory arthritis have begun to blend together into a chronic, painful, polyarticular inflammatory synovitis in his hands, elbows, knees, and feet from which he has come to your office seeking relief.

64 Gout: Findings He has chronic swelling, synovitis,, and deformities reminiscent of rheumatoid arthritis Numerous tophi scattered on arms, legs, and ears Serum creatinine is 1.8 Uric Acid 10.2

65 You face two problems: What to do to treat his symptoms acutely? How to manage his now chronic arthropathy in the longer-term?

66 In the acute setting, the best approach to managing this patient s s symptoms would be to start?: A. Indomethacin 75 mg-100mg PO TID B. Colchicine 0.6 mg PO q2hr until he improves C. Prednisone 20 mg PO daily D. Allopurinol 300 mg PO daily Indomethacin 75 mg % 25% 25% 25% Colchicine 0.6 mg PO q2.. Prednisone 20 mg PO daily Allopurinol 300 mg PO daily

67 Managing the Acute Symptoms In the acute setting, the best approach to managing this patient s s symptoms would be to start?: A. Indomethacin 75 mg-100mg PO TID B. Colchicine 0.6 mg PO q2hr until he improves C. Prednisone 20 mg PO daily D. Allopurinol 300 mg PO daily

68 Chronic Management The patient is started on appropriate therapy to manage his pain and inflammation, however, you correctly feel that this is not an adequate long term solution to manage his disease and worry about side effects from therapy. Although his synovitis initially improves, you are finding it difficult to taper his medicine because of the arthritis flares, and his tophi and joint damage are progressing nonetheless.

69 Once adequately prophylaxed,, you now decide to treat his chronic symptoms of gout by: A. Starting allopurinol 300/day B. Colchicine 0.6 mg/day C. Probenecid 250 mg twice daily D. None of the above Starting allopurinol 300/day 25% 25% 25% 25% Colchicine 0.6 mg/day Probenecid 250 mg twic... None of the above

70 Managing the Chronic Disease Once adequately prophylaxed,, you now decide to treat his chronic symptoms of gout by: A. Starting allopurinol 300/day B. Colchicine 0.6 mg/day C. Probenecid 250 mg twice daily D. None of the above

71 Management of Chronic Gout in a Challenging Patient You decide to start allopurinol therapy at low dose because of his renal insufficiency - beginning with 100 mg every other day and progressing over SEVERAL months to as much as 300 mg every other day. The patient develops a fever, rash, and elevated LFTs thought secondary to allopurinol hypersensitivity, you discontinue the medication. The patient recovers fully and now has a uric acid level of 9.1. His chronic destructive arthritis continues unabated.

72 Your next Best Step is A. To try allopurinol desensitization B. Ban him from eating all foods with purines C. Go to the literature in hopes of finding a promising alternative D. Fret To try allopurinol desensi... 25% 25% 25% 25% Ban him from eating all... Go to the literature in ho... Fret

73 Your next Best Step is A. To try allopurinol desensitization B. Ban him from eating all foods with purines C. Go to the literature in hopes of finding a promising alternative Fret D. Fret

74 Febuxostat First new treatment in 40 years in chronic management of gout NON-PURINE inhibitor of xanthine oxidase Theoretically safe to use in patients with allopurinol reactions Been studied in patients with mild renal insufficiency Dosed at 40-80mg/once daily

patients achieving uric acid <6 Greater reduction in serum uric acid levels Used in

75 Comparison of Febuxostat to Allopurinol Becker et al. NEJM mg and 120 mg of febuxostat superior to allopurinol 300mg day Percent of patients achieving uric acid <6 Greater reduction in serum uric acid levels Used in patients with mild-moderate moderate renal insufficiency (SCr( < in this study) Safe for patients with allopurinol reactions

76 Similar reduction in number of gout flares for both agents Becker et al. NEJM 2005

77 Summary Respect IHD in RA and SLE Suspect it Treat it aggressively (Don t t forget about opportunistic infections) OCPs appear safe in SLE patients Vaccines recommended Beware live vaccines if patient on a biologic Consider febuxostat for patients who do not tolerate allopurinol

78 Memorial Day Thoughts to soldiers, vets and families

79 QUESTIONS

Controversies in Women s Health: Clinical Dilemmas in Arthritis

Controversies in Women s Health: Clinical Dilemmas in Arthritis Jonathan Graf, M.D. Assistant Professor of Medicine, UCSF Division of Rheumatology, SFGH December, 2008 Approximate Prevalence of Rheumatic