Controversies in Women s Health: Clinical Dilemmas in Arthritis

Transcription

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

2 Approximate Prevalence of Rheumatic Disease F:M ratios Systemic Lupus Erythematosus 9:1 Sjogren s Syndrome 9:1 Scleroderma 3-7:1 Inflammatory Myopathies 2-5:1 Rheumatoid Arthritis 3:1 Wegener s Giant Cell Arteritis 1:1 (M) 1:1 (F) Ankylosing Spondylitits 1:2-5

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

4 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 s & 30 s Incidence has tripled since 1970 s s to 5.56/100,000 population

5 SLE: ACR Criteria: 4 of 11 Criteria without better explanation (Not diagnostic, but help to classify patients for studies) Malar Rash Discoid Rash Photosensitivity Oral Ulcers Arthritis Serositis Renal Disorder

6 SLE Criteria Cont. Hematologic Disorder Immunologic Disorder ANA Neurologic Disorder

7 Malar Rash Fixed malar distribution of erythema,, flat or raised

8 Discoid Rash Erythematous raised patches with keratotic scaling and follicular plugging; some atrophic scarring in chronic lesions

9 DLE - Old

10 Photosensitivity Skin rash as an unusual reaction sunlight, by patient history or physical examination

11 Oral Ulcers Oral or nasopharyngeal ulcers, usually painless, observed by a physician

12 Arthritis Non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

13 Other SLE Criteria 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

14 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)

15 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

16 Positive ANA An abnormal titer of ANA in the absence of drugs known to be associated with drug- induced lupus syndrome

17 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

18 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.

19 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

20 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

21 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

22 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

23 SLE: Useful facts of which a primary care physician should be aware 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 by questions like this: A 40 year old woman with a six year history of lupus develops fever, worsening respiratory failure, and infiltrates on chest CT. C Your next best step is to: A. Start prednisone therapy immediately B. Check her anti-dsdna titer C. Arrange for an open lung biopsy D. Start antibiotics, pan culture, and arrange for bronchoscopy

24 SLE: Useful facts of which a primary care physician should be aware 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 by questions like this: A 40 year old woman with a six year history of lupus develops fever, worsening respiratory failure, and infiltrates on chest CT. C Your next best step is to: A. Start prednisone therapy immediately B. Check her anti-dsdna titer C. Arrange for an open lung biopsy D. Start antibiotics, pan culture, and arrange for bronchoscopy

25 SLE: Useful Facts of which the Internist should be Aware 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 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!!!!

26 SLE: Role of Rheumatologists and 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 SLE 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 SLE patients

27 Primary Care management of active SLE Often using specialists to help co-manage pts patients Establish diagnosis Assessment of levels of disease activity Management of disease specific activity and use of immunuo- supressive therapy Managing end organ damage ESRD, Pulmonary HTN, etc.. Monitoring toxicity of therapy Low WBC: disease activity or toxicity of therapy

28 Stable SLE: Routine Care Monitoring of disease activity at regular intervals Often with help of subspecialist (q months) Frequently can preempt more severe clinical manifestations Directed SLE H&P (Skin, joints, lungs, etc ) Routine Lab monitoring of CBC, complements, creatinine, urinalysis, urine protein quantification, anti-dsdna abs. Routine lab monitoring for toxicity of therapy (LFTs( for methotrexate,, etc..)

29 SLE: Health Care Maintenance Routine medical care, age appropriate cancer screening, gynecologic exams Avoidance of UV light and use of Sunscreens (SPF >30) Eye exams for patients on anti- malarials Bone density screening for steroid-induced induced osteoporosis Cardiovascular risk factor management

30 Mitigation of Cardiovascular Risk in SLE Abstinence from smoking Aggressive blood pressure management (? pre-htn) Aggressive management of lipids Manage LDL, and Tchol/HDL ratio as if at highest Framingham CV risk Encouraging aerobic exercise Addressing all potential CV symptoms promptly, even in younger females

31 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.

32 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

33 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

34 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.

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

36 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

37 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

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

39 SELENA: Results

40 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

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

42 Mean SLEDAI Lupus Activity

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

44 HRT and Lupus Flare Sanchez-Guerrero A&R 2007 Buyon J. Annals of Internal Medicine 2005 SLEDIA 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

45 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

46 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.

47 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

48 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

49 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

50 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

51 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 ( )

52 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

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

54 Question #4 Winter is fast approaching, and you are busy vaccinating all of your patients. You are currently seeing your patient with SLE, and you remember that vaccinations in patients with SLE has been controversial in the past.

55 Question #4 Which of the following vaccines would be definitively recommended for your patient at this time? A. Pneumococcal B. Influenza C. Zoster Vaccine D. A&B E. None of the Above

56 Question #4 Which of the following vaccines would be definitively recommended for your patient at this time? A. Pneumococcal B. Influenza C. Zoster Vaccine D. A&B E. None of the Above

57 Vaccinations and SLE: Theoretical Risks Antigen and adjuvant in vaccine preparations are immunostimulatory: : may cause SLE to flare Anecdotal reports of SLE onset after vaccinations SLE and its therapy are immunosupressive vaccines won t t work

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

59 SLE and Vaccinations Vaccination with influenza vaccine does not increase SLE flares and is sero-protective in most SLE patients 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