grand rounds: zebra or duck kathryn dao, md arthritis center presbyterian hospital june 29, 2005

Grand Rounds: Grand Rounds: Zebra or DuckZebra or Duck

Kathryn Dao, MDKathryn Dao, MD

Arthritis CenterArthritis Center

Presbyterian Hospital Presbyterian Hospital

June 29, 2005June 29, 2005

Common DxCommon Dx

Common S/SxCommon S/Sx

Uncommon DxUncommon Dx

Common S/SxCommon S/Sx

Common DxCommon Dx

Uncommon S/SxUncommon S/Sx

Uncommon DxUncommon Dx

Uncommon S/SxUncommon S/Sx

Case: UnknownCase: Unknown

CC: Joint pain, +ANAHPI: MS is a 44 y.o. WF with hyperlipidemia

who developed ankle pain and swelling suddenly after she finished a ballet recital. She went to her PCP for evaluation and over the next month she was given in series ibuprofen, naproxen, and Vioxx. The symptoms persisted; she returned to her PCP who drew labs and found an abnormal ANA.

HPI (cont’d): She was given a Medrol dose pack and a referral to rheumatology. The steroids gave her partial relief. She stated the pain progressed to her hands, knees, and ankles. Pain scale 4 out 10. AM stiffness 15min- 2 h. Activity and heat improve her symptoms. She denied sick contacts, recent travel, weight loss, fever, apthous ulcers, GI/GU complaints, and photosensitivity.

Associated symptoms: ??Raynaud’s phenomenon, memory difficulties, fatigue, headache, insomnia, “bone pain”, myalgias, depressive symptoms, weight gain 5# since on steroids

PMH: Hyperlipidemia, Acne, Allergic Rhinitis

Meds: Allegra, Lipitor, Minocin, Vioxx, Sudafed

Allergies: None

SX: Patient is married with 2 children; she is a full time homemaker whose hobbies include the ballet and interior design; no tobacco/EtOH/IVDU, STD risks.

FX: Mother with arthritis, Brother with UC

PE: T 98.6 BP 110/72 HR 78 RR16 weight 126 lb

G: WD female NAD

HEENT: No scalp lesions, eyes/ears normal, OP clear Skin: no malar rash, psoriatic plaques, discoid lesions Neck: No LAD/TM. Supple with FROM Pulmonary, CV, Abd: normal

SkM: +synovitis LPIP2,3, right wrist, bilateral ankles L>R. Elbows, shoulders, hips, knees normal. 2+ pedal edema ROM good in all joints. 6 out 18 tender points present. No nodules or deformity.

Labs: from PCP (6/29/04)-

5.6 14.1 261 138 108 12 102 _ 40.9 4.1 24 0.8

Ca 10.6 TP 7.4 Alb 4.0 AST 18 ALT 20 ALP 100

Total chol: 190 TG 194 TSH 1.4

ANA 1:1280, RF neg, CRP 1.2 mg/dL, CK 35

From Rheum visit (7/13/04)8.5 14.9 246 137 109 13 88 _ 40.9 4.1 24 0.8


ANA 1:640, Sm/RNP neg, dsDNA Ab neg, C3, C4 nl RF neg, CCP Ab neg, HLA-B27 neg, ACE normalParvo-B19 IgM neg, HBsAg neg, HCV Ab negESR 1, CRP < 0.1

Hand/feet x-rays : normalBone scan: neg

•Possible reactive arthritis other DDx being entertained: RA, palindromic rheumatism, SLE, sarcoidosis, seronegative spondyloarthropathy with peripheral arthritis, drug-induced lupus, metabolic disorder, infectious/neoplastic not likely

•Elevated LFTs—possible from NSAID use. Patient advised to minimize use of NSAIDs and to stop Minocin. Repeated LFTs normal.

•Patient given prednisone 10 mg/d with followup in 4 weeks.

Patient returned with complete resolution of joint symptoms with the prednisone. Over the following month, she was able to wean herself off steroids completely. Headaches, myalgias, fatigue, memory difficulties, insomnia, depression still persistent.

6 months later, joint symptoms returned—pain and stiffness in feet, ankles, knees, and hands. Now has right thumb numbness. Recent URI illness which resolved with antibiotics. AM stiffness 60 min. Exam: No rash; +synovitis in LPIP2-4, RPIP2, left wrist, and right ankle

From Rheum visit (9/13/04)5.8 12.9 310 137 109 13 88 _ 37.9 4.1 24 0.8


ESR 4, CRP 0.4

Review pertinent data/abnormalities

•Acute onset inflammatory oligoarticular process with pitting edema progressed to polyarticular process; fatigue, memory problems, myalgias, headaches, bone pain

•+ANA

•Ca 10.6 TP 7.4 Alb 4.0 AST 18 ALT 20 ALP 100•Ca 9.8 TP 7.2 Alb 3.8 AST 16 ALT 50 ALP 102•Ca 10.4 TP 7.2 Alb 3.9 AST 18 ALT 22 ALP 102

PTH 98

24 hour urine calcium elevated

DEXA: Wards triangle -2.7, Hip -2.4, L-spine -2.0

24-0H vitamin D normal.

Sestimibi scan:

Primary Primary HyperparathyroidismHyperparathyroidism

Role of PTH:Role of PTH: regulate serum calcium and regulate serum calcium and bone metabolismbone metabolism

Function: Function:

1. Stimulate renal tubular Ca reabsoption1. Stimulate renal tubular Ca reabsoption

2. Bone resorption2. Bone resorption

3. Convert calcidiol to calcitriol which 3. Convert calcidiol to calcitriol which stimulates intestinal calcium absorptionstimulates intestinal calcium absorption

NEJM 2000;343(25):1863-75.


Incidence: more prevalent in persons Incidence: more prevalent in persons > 50 y.o.> 50 y.o.

1/1000 males1/1000 males

2-3/1000 females 2-3/1000 females Underlying cause in 85% of patients is a single Underlying cause in 85% of patients is a single

adenoma (less than 15% due to multiple adenoma (less than 15% due to multiple adenomas or glandular hypertrophy of all 4 adenomas or glandular hypertrophy of all 4 glands; <0.5% from malignancy, MEN glands; <0.5% from malignancy, MEN syndromes, FHH)syndromes, FHH)


NIH consensus panel classify patients NIH consensus panel classify patients as as

symptomatic vs. asymptomaticsymptomatic vs. asymptomatic Symptomatic: (15-20%)- from hypercalcemiaSymptomatic: (15-20%)- from hypercalcemia

Bones, stones, groans, moans, fatigue overtonesBones, stones, groans, moans, fatigue overtones

(osteitis fibrosa cystica, kidney stones, DI, (osteitis fibrosa cystica, kidney stones, DI,

GI/CV/neuromuscular dysfunction)GI/CV/neuromuscular dysfunction)

Asymptomatic (75-80%)Asymptomatic (75-80%)

(HTN, fatigue, PUD, normocytic anemia, weakness, depression, (HTN, fatigue, PUD, normocytic anemia, weakness, depression, anxiety, cognitive dysfunction)anxiety, cognitive dysfunction)

NIH Consens Statement 1990 Oct 29-31;8(7):1-18.


Rheumatologic manifestations of Rheumatologic manifestations of PHPTHPHPTH

1983 Retrospective study of 34 patients with rheumatic symptoms:1983 Retrospective study of 34 patients with rheumatic symptoms: myalgias (41%)myalgias (41%) arthralgia/arthritis affecting large joints (32%)arthralgia/arthritis affecting large joints (32%) erosive synovitis mimicking RA (5%)erosive synovitis mimicking RA (5%) radiologic abnormalities (24%)radiologic abnormalities (24%)

1978 Prospective controlled study of PHPTH: 1978 Prospective controlled study of PHPTH: 8 out of 26 had chondrocalcinosis, 2 without 8 out of 26 had chondrocalcinosis, 2 without

chondrocalcinosis had documented pseudogoutchondrocalcinosis had documented pseudogout

Postgrad Med J 1983;59(690):236-40 J Rheumatol 1978 Winter;5(4):460-8


Differential Diagnoses:Differential Diagnoses:Elevated Calcium with elevated PTHElevated Calcium with elevated PTH

DDx: DDx: HCTZHCTZ

LithiumLithium

FHH (Uca:cr <0.01)FHH (Uca:cr <0.01)

33oo Hyperparathyroidism (ESRD) Hyperparathyroidism (ESRD)

Normal Calcium with elevated PTHNormal Calcium with elevated PTH

DDx: DDx: Vitamin D deficiency (2Vitamin D deficiency (2oo HyperPTH) HyperPTH)


Elevated serum calcium

Recheck labs with albumin and correct or check ionized

calciumEvaluate for secondary causes (medications)

Check intact PTHlow high

Malignancy Granulomatous Dz Adrenal Insufficiency Vitamin A/D Toxicity Hyperthyroid Milk Alkali Syndrome Immobilization

Check 24 U CrCl, calcium, 25-OH vitamin D

low

FHH CRI

high

Primary HyperPTH


Once Primary HyperPTH established, check:Once Primary HyperPTH established, check: Bone Mineral Density at all 3 sites:Bone Mineral Density at all 3 sites:

distal radius, L-spine, hipdistal radius, L-spine, hip Surgery vs. conservative managementSurgery vs. conservative management

Note: Sestimibi parathyroid scan (optional)Note: Sestimibi parathyroid scan (optional)—— sensitivity 83%, PPV 93%sensitivity 83%, PPV 93%


1985 Longitudinal cohort study of 47 patients with PHPTH 1985 Longitudinal cohort study of 47 patients with PHPTH followed X 5 years; 34% experienced complication from followed X 5 years; 34% experienced complication from PHPTH—PUD (8), RI (5), renal stone (1), hypercalcemic PHPTH—PUD (8), RI (5), renal stone (1), hypercalcemic crisis (1), ventricular conduction defect (1)crisis (1), ventricular conduction defect (1)

1991 Cohort study of 176 patients with sustained 1991 Cohort study of 176 patients with sustained hypercalcemia followed 15 years. Survival significantly lower hypercalcemia followed 15 years. Survival significantly lower from CV complicationsfrom CV complications

2001 Longitudinal study with matched controls in 172 patients 2001 Longitudinal study with matched controls in 172 patients with PHPTH X25 years, increased mortality in patients with PHPTH X25 years, increased mortality in patients <70y.o (p=0.015) with CV disease representing deaths; HZ <70y.o (p=0.015) with CV disease representing deaths; HZ 1.72 (95%CI, 1.24-2.37); trend over time of normocalcemia in 1.72 (95%CI, 1.24-2.37); trend over time of normocalcemia in patients (NS)patients (NS)

Surgery 1985;98(6):1064-71. J Bone Miner Res 1991;(Suppl 2):S111-6. Surgery 2001;130(6):978-85.

Conservative Management:


2000 Prospective surgical cohort X 10 years- surgical cure obtained 2000 Prospective surgical cohort X 10 years- surgical cure obtained in 97.7% after initial cervical exploration; 54% recovered fully from in 97.7% after initial cervical exploration; 54% recovered fully from hypercalcemic syndrome in the 1hypercalcemic syndrome in the 1stst month, 84% patients within first month, 84% patients within first 2 years. No recurrence found2 years. No recurrence found

2004 Prospective randomized controlled study 53 patients: 25 SGY, 2004 Prospective randomized controlled study 53 patients: 25 SGY, 28 Med Rx followed for 2 years–BMD improved at all sites with 28 Med Rx followed for 2 years–BMD improved at all sites with SGY, but only in L-spine and radius with Med Rx; in SF-36 of Med SGY, but only in L-spine and radius with Med Rx; in SF-36 of Med Rx decline in social functioning, physical problem, emotional Rx decline in social functioning, physical problem, emotional problem, energy, and health perception problem, energy, and health perception

2004 Controlled cohort study 3213 HPTH followed 20 years – 60% 2004 Controlled cohort study 3213 HPTH followed 20 years – 60% had surgery, 40% Med Rx; SGY risk for fx (HZ 0.69), PUD (HZ had surgery, 40% Med Rx; SGY risk for fx (HZ 0.69), PUD (HZ 0.59), death (HZ 0.65), increased episodes of renal stones (HZ 0.59), death (HZ 0.65), increased episodes of renal stones (HZ 1.87). Survival in both cohorts decreased relative to general pop. by 1.87). Survival in both cohorts decreased relative to general pop. by 2.1-2.7 years; SGY not change CV event rate, psychoses, myalgias.2.1-2.7 years; SGY not change CV event rate, psychoses, myalgias.

World J Surg 2000;24(5):564-9. J Clin End Metab. 2004;89(11):5415-22 . J Intern Med. 2004;255(1):108-14

Surgical resection:


Old and New Criteria for Surgery of ASx PatientsOld and New Criteria for Surgery of ASx Patients

VariableVariable 1990 NIH1990 NIH 2002 NIDDK2002 NIDDKsCa concentrationsCa concentration 1.0-1.6 mg/dL above nl1.0-1.6 mg/dL above nl 1.0 mg/dL above nl 1.0 mg/dL above nl

24 h Urine calcium24 h Urine calcium >400 mg>400 mg >400 mg>400 mg

Reduction in CrClReduction in CrCl 30%30% 30%30%

BMDBMD Z score <-2.0 in forearmZ score <-2.0 in forearm T score <-2.5 any siteT score <-2.5 any site

AgeAge <50 y.o<50 y.o <50 y.o.<50 y.o.

NIH Consens Statement 1990 Oct 29-31;8(7):1-18.

J Bone and Mineral Res 2002; 17 (Suppl 2):N2-N11.


Old and New Guidelines for Medical ManagementOld and New Guidelines for Medical Management

VariableVariable 1990 NIH1990 NIH 2002 NIDDK2002 NIDDKsCa monitoringsCa monitoring every 6 monthsevery 6 months every 6 month every 6 month

24 h Urine calcium24 h Urine calcium every yearevery year not recommendednot recommended

Serum creatinineSerum creatinine every yearevery year every yearevery year

CrClCrCl every yearevery year not recommendednot recommended

BMDBMD every yearevery year every year all 3 sitesevery year all 3 sites

Abdominal radiographAbdominal radiograph every yearevery year not recommendednot recommended

Dietary guidelinesDietary guidelines hydrationhydration intake of 1000-1200mg Caintake of 1000-1200mg Ca

with 400-600IU vit Dwith 400-600IU vit DNIH Consens Statement 1990 Oct 29-31;8(7):1-18. J Bone and Mineral Res 2002; 17 (Suppl 2):N2-N11.


Medical therapy:Medical therapy: Bisphosphonates Bisphosphonates Estrogens/raloxifeneEstrogens/raloxifene Calcimimetic DrugsCalcimimetic Drugs

Primary Primary HyperparathyroidismHyperparathyroidism Etidronate: Etidronate: 2002 Japanese study 22 patients (1 yr 2002 Japanese study 22 patients (1 yr

f/u)f/u)

OutcomeOutcome Etidronate (9)Etidronate (9) Surgery (13)____ Surgery (13)____

LS-BMDLS-BMD +10%+10% (p<0.03)(p<0.03) +20% (p<0.01)+20% (p<0.01)

Fracture rateFracture rate UnchangedUnchanged UnchangedUnchanged

Alendronate vs. Placebo: Alendronate vs. Placebo: 2001: Italian Study2001: Italian Study of 26 pts.: alendronate 10 mg/d after 2 years, of 26 pts.: alendronate 10 mg/d after 2 years, increase BMD of LS (+8.6%), Hip (+4.8%), T-BMD (+1.2%)increase BMD of LS (+8.6%), Hip (+4.8%), T-BMD (+1.2%)

2003: Chinese Study2003: Chinese Study of 40 postmenopausal patients followed 48 of 40 postmenopausal patients followed 48 weeks; alendronate increase BMD femoral neck +4.17%, LS +3.79%weeks; alendronate increase BMD femoral neck +4.17%, LS +3.79%

2004 Canadian Study2004 Canadian Study 44 patients (2 yr f/u, 44 patients (2 yr f/u, placebo crossoverplacebo crossover at 1 at 1 year): BMD of LS (+6.85%, year): BMD of LS (+6.85%, 4.14.1%), hip (+4.01%, %), hip (+4.01%, 1.71.7%), distal radius %), distal radius (NS)(NS)

Gerontology.2002;48(2):103-8 J Bone Min Res 2001;16(1):113-9 J Clin Endoc Metab 2003;88(2):581-7 J Clin Endoc Metab 2004;89(7):3319-25


Estrogen: Estrogen: 1996 Australian study:1996 Australian study: 15 patients (5 ERT, 10 SGY); ERT BMD 15 patients (5 ERT, 10 SGY); ERT BMD LS (+5.3%), femoral neck (+5.5%), no sig change between ERT LS (+5.3%), femoral neck (+5.5%), no sig change between ERT and SGY; SGY patients normalized serum calcium level and SGY; SGY patients normalized serum calcium level

2000 New Zealand study2000 New Zealand study: 23 patients (4 yr f/u)- RDBPCT with : 23 patients (4 yr f/u)- RDBPCT with 0.625 mg conj estrogen with medroxyPG; HRT increase BMD 0.625 mg conj estrogen with medroxyPG; HRT increase BMD LS (+7.5%), femoral neck (+7.4%), forearm (+7.0%), total body LS (+7.5%), femoral neck (+7.4%), forearm (+7.0%), total body (+4.6%) (+4.6%)

Raloxifene Raloxifene 2003 NY study2003 NY study: 18 patients drug vs placebo X 8 weeks with 4 : 18 patients drug vs placebo X 8 weeks with 4 week washout; calcium level decreased (10.8 to 10.4 mg/dL) as week washout; calcium level decreased (10.8 to 10.4 mg/dL) as well as markers of bone resorption and formation (osteocalcin well as markers of bone resorption and formation (osteocalcin 11.4 to 9.9 nm/L; sNTX 21.2 to 17.3 nm/L). No change to PTH, 11.4 to 9.9 nm/L; sNTX 21.2 to 17.3 nm/L). No change to PTH, 1,25-OH D3 or urinary Ca1,25-OH D3 or urinary Ca

Osteoporosis Int 1996;6(4):329-33. Arch Int Med 2000;160(14)2161-6 J Clin Endo Met 2003;88(3):1174-8


Cinacalcet (calcimimetic)Cinacalcet (calcimimetic)2003 UCSF RDBPCT2003 UCSF RDBPCT: 22 patients, 2 week of drug followed by 1 : 22 patients, 2 week of drug followed by 1 week observation. Cinacalcet (30, 40 or 50 mg bid) v. placebo. week observation. Cinacalcet (30, 40 or 50 mg bid) v. placebo. Serum calcium normalized on second dose of day 1of all Serum calcium normalized on second dose of day 1of all treated with drug and remained within normal range. PTH treated with drug and remained within normal range. PTH decreased by 50% with active treatment.decreased by 50% with active treatment.

2004 Indiana Univ RDBPCT2004 Indiana Univ RDBPCT: 78 patients; 12 weeks therapy : 78 patients; 12 weeks therapy with 28 week followup. Cinacalcet 73% reduction in sCa vs with 28 week followup. Cinacalcet 73% reduction in sCa vs placebo 5%; reduction in PTH with treatment (by 7.6%) vs. rise placebo 5%; reduction in PTH with treatment (by 7.6%) vs. rise in PTH in placebo (by 7.7%). No change in BMD, increase in in PTH in placebo (by 7.7%). No change in BMD, increase in bone resorption and formation markersbone resorption and formation markers

2005 Arizona RDBPCT2005 Arizona RDBPCT Cinacalcet in 2 Cinacalcet in 2oo HPTH: 14 patients with HPTH: 14 patients with ESRD, 26 week therapy. PTH decreased, BMD increased femur ESRD, 26 week therapy. PTH decreased, BMD increased femur (p<0.05), no effect on L-spine(p<0.05), no effect on L-spine

J Clin End Met 2003;88(12):5644-9 Nephrol Dial Transpl 2005;20(6):1232-7 J Clin End Metab 2005;90(1):135-41

MS underwent surgical exploration or her neck; a parathyroid adenoma was resected from the left inferior aspect. Biochemical confirmation was made by a 67% drop in the intact PTH within 5 minutes consistent with the removal of autonomously functioning parathyroid tissue.

Will her polyarticular synovitis resolve…

... or does she have an underlying CTD???

grand rounds: zebra or duck kathryn dao, md arthritis center presbyterian hospital june 29, 2005

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