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Rheumatoid Arthritis

disease
and related comorbidities.

Ashoka Benedict Gomes. 02/02/17.


PHA5597
History of present illness:

ST is a 90 year female with history of Alzheimer’s Dementia, Rheumatoid Arthritis, CKD, anemia, hypothyroidism, unsteady
gait.
She has had Rheumatoid Arthritis since 2009 and was on methotrexate (MTX) till 2011. MTX caused leucopenia and anemia
which needed Packed RBC transfusions x2. She was switched to Remicade IV 100 mg/kg/ 8 weeks (1.5mg/kg/8 weeks).
Her chief complaint is that she still has continued low back pain and knee pain, but can walk with a walker. She reports that
she is independent and takes her medication regularly.

Past Medical History (PMH):


Hypothyroidism. 2001 Surgical History:
Rheumatoid arthritis. 2009 Ankle repair.
Alzheimer's disease. 2010 Hysterectomy.
Chronic Kidney disease. 2010
Anemia. 2010

Current Medical Problem List:


1- Lower back pain and Knee pain uncontrolled.
2- Lab values for TSH are low for an elderly patient and should be increased.
3- Absence of glucocorticoid for RA flares.
Family History/Social History:
Health Plan: Medicare part D (VA benefits).
Primary Provider: VA medical center.
Occupation: Retired VA.
Family History: No family history of diabetics or other chronic disease states.
Race: Caucasian.
Smoking: None
Alcohol: None
Illicit drug use: None
Hobbies: Watching TV.

Allergies: NKDA.
Adherence: Patient is independent for ADL.
Immunization: Uptodate.
Current Medications:
Procrit 30,000 units monthly for hemoglobin
Citalopram 20mg daily
Colace 100mg twice daily
Donepezil 10mg daily
Ferrous fumarate: 325 MG daily
Hydroxychloroquine sulphate 200mg daily
Levothyroxine 100 mcg daily
Mirtazapine 7.5mg daily at bedtime
Remicade (Infliximab) 100mg (1.5mg/kg) IV Q 8 weeks

Review of Symptoms:
General: ST is a 90 year caucasian female; she is 5 feet 5 inches and weighs 146 lbs, she reports low back pain and knee
pain, she is ADL, elderly and uses a walker.
Vital signs: T-96.9 P-76 RR-20
BP (SITTING)-140/74 mmHg BP(STANDING)-150/70 mmHg O2sat- 94% RA
WT- 146 lbs (66.2kg) HT- 5.5 BMI-
24.43
WD,WN female in NAD.
HEENT: Head is atraumatic, normocephalic. PERL, EOMI (eye).
Neuro: Alert, oriented x2 to person/place. Cranial nerves 2-12 intact. No focal deficits.
No tremors. Memory: Impaired.
Gait: small steps, slow, unstable.
Continued on next slide….
Review of symptoms:
Blood work: HGB=11.0, Folate=22.8, Ferritin=24, WBC=9, TSH=0.4, Free T4=2.2.
Respiratory: Unlabored, good effort, CTAB (no internal sounds).
External canals normal, tm, normal
Oropharynx: Moist mucous membranes.
Cardiovascular: RRR , no murmurs Edema: Negative.
Abd : soft, NT, no masses palpable. BS+ (normal bowel sounds)
Renal: Scr=1.7. BUN=30 mg/dl eGFR=26 (CKD). Liver: AST=47, ALT=27.
Psych : Mood /Affect appropriate.

Identification of Drug Therapy Problems:


1- Indication for a drug but drug not prescribed properly. (Remicade (Infliximab) dose or frequency does not adequately control
joint pain symptoms).

2- Indication for a drug but not prescribed properly. (TSH levels are on the lower side while free T4 is high, this indicates likely
irregular or double dosing and in elderly patients a dose reduction can improve TSH function and be cardioprotective).

3- Indication for a drug but drug not prescribed. (Absence of glucocorticoid for RA flares-recommended less than 10 mg/day of
prednisone).
Drug Therapy Problem #1:

Indication for a drug but drug not prescribed properly.

Remicade dose or frequency does not adequately control joint pain symptoms.
Possible to decrease frequency of dosing to less than 8 weeks (6 weeks) or increase dose (not preferred).

Based on the ACR guidelines for this patient and looking at the benefits based on clinical research a decrease in frequency will be
more efficacious and less risk of infections as she will be monitored more frequently with a lower dose.
Pathophysiology:
Rheumatoid arthritis(RA) is an autoimmune disease that has both an intra-articular and systemic component. T-cells, B-cells,
macrophages along with secreted cytokines (TNFa, IL-17, IL-6, IL-1) cause the destruction of the joints.

Though the exact mechanism of RA development is unclear, the progression of the disease is dependent on many cells. The
first events are by antigen presenting cells (APC), dendritic cells, macrophages and B-cells to T-cells causing the infiltration of
CD4+ t-cells in the synovial membrane and secretion of IL-2 and IFN-g.

B-cells also produce autoantibodies and cytokines. Both activated B-cells and T-cells secrete cytokines and chemokines that
continue to recruit more B-cells, macrophages and T-cells causing more damage.

Macrophages secrete high amounts of proinflammatory cytokines TNFa, IL-1 and IL-6. Synoviocytes also secrete MMP’s
(matrix metalloproteinase) which degrade the cartilage and bone when stimulated by TNFa, IL-1 or IL-6.

These complex immune interactions also increase the risks for Cardiovascular Disease (CVD), Anemia, Bone loss
(osteoporosis) fatigue and depression in RA patients.
Intervention to resolve drug therapy problem: for #1
Recommend changing remicade (infliximab) 100 mg IV frequency of dosing to every 6 weeks(ref=1,2,3,4). Patient will be
monitored every 12 weeks using the Rapid3 pain test.
Rationale for intervention: Based on the ACR guidelines for this patient and looking at the benefits based on clinical research a decrease
in frequency will be more efficacious and less risk of infections as she will be monitored more frequently with less dose.

Pharmacology of Remicade (infliximab):


Remicade (infliximab) is a monoclonal antibody composed of a murine antigen component and a human Fc Ig component
directed against TNFa.

Remicade (infliximab) binds to the soluble and transmembrane forms of TNFa preventing binding of TNFa to its receptor.
Thus the inducing actions of the cytokine TNFa on proinflammatory cytokines, leukocyte migration, fibroblast/neutrophil
activation, and other proinflammatory processes are blocked.

Pharmacokinetics/dynamics of Remicade (infliximab):


Remicade (infliximab) distributes mainly in the vascular compartment. Its half life is 8 - 9.5 days and there is no need to adjust
dosing for hepatic or renal dysfunction.
A study has shown that serum Remicade (infliximab) levels need to be greater than 1.3mg/L for clinical efficacy (ref=12),
however monitoring of serum levels is not recommended.

Preparation/administration/stability/cost of Remicade (infliximab): Remicade (infliximab) is only available as a Lyophilised


powder for IV administration. Once reconstituted use within 3 hours and further dilute with 250ml of 0.9% sodium chloride for
injection, then administer over greater than 2 hours. Its cost is high.
Scientific/Expert opinion: #1
1- Titration of infliximab treatment in rheumatoid arthritis patients based on response patterns. M. Flen, M. Creemers, P. van
Riel. Rheumatology. 16 June 2006:46:1:146-149.
Objective: The authors evaluated the effects of increasing the doses of infliximab v/s increasing the frequency of dosing in RA patients not
responding adequately to standard 3 mg/kg every 8 week treatments.

Methods: 76 RA patients were given standard 3 mg/kg treatment at weeks 0,2,6 and 8 weeks thereafter. Between weeks 14 and 22,
DAS28 scores were measured and patients were put into groups of good responders, moderate responders or nonresponders. At week 22
doses were either increased (6 mg/kg/ 8 weeks) or frequency was decreased. All groups were observed till week 38.

Results: At week 14: 22 patients were put as good responders (they finished the study at week 38 with not much changes), 26 patients
were classified as moderate responders and 21 patients were classified as nonresponders, 7 stopped the study.
Of the 26 patients (moderate responders) 8 dropped out, and rest were put in 3 groups A, B, C (n=6 /group),
A- In patients that had disease flares the frequency of dosing was reduced, the DAS28 scores reduced from 5.1 at week 22 to 3.6 at
week 38 (p<0.005) with a mean interval= 5.6 weeks of treatment.
B- In patients with stable disease the dose was increased (6+ mg/kg/8 weeks), the DAS28 scores reduced from 4.1 at week 22 to 3.6 at
week 38 (p<0.04) with a mean dose increase to 7.3mg/kg/8 weeks (from 4mg/kg/8w).
C- 6 patients (n=6) improved to good responders and remained good till week 38.

Conclusion: Based on the results it was concluded that a dosing frequency reduction would be more efficacious v/s a dose increase in
infliximab though both are effective.
Scientific/Expert opinion: #2
2- TNFa therapy in rheumatoid arthritis: Correlation of TNF-a serum levels with clinical response and benefit from changing
dose or frequency of infliximab infusions. Edrees F, Misra N, Abdou I. Clinical and Experimental Rheumatology, July 2005,
Vol:23:4:469-474.

Objective: To evaluate if serum TNFa levels are useful in treatment decisions and to evaluate if a dose increase or frequency increase is
more clinically effective .

Methods: 55 RA patients were given standard 3 mg/kg infliximab treatment. They were evaluated using a Richie score index for disease
activity and put into 2 groups (Richie scores =<10 non-active group(n=30) OR >10 was the active group (n=25)).
Serum TNFa levels were measured before infliximab infusion and 9-11 days after infusion.

Results: 31 patients that did not respond to standard 3mg/kg/8weeks infliximab treatment were divided into 3 groups.
Group S= had 13 patients with no change in infliximab dose or frequency;
Group D= had 7 patients with an increase in their infliximab dose and
Group F= had 11 patients with a decrease in dosing frequency to every 6 weeks.
Only Group F (decreased frequency of infliximab dosing) showed a significant decrease in Richie score index (12.9 preinfusion to 4.9 post
infusion p<0.0349) and also had the most ACR20 improvement (36%). Group D (increase in their infliximab dose) had a Richie score index
change from 12.8 preinfusion to 8 postinfusion and ACR20 improvement of 29%.
Pre and post infusion serum TNFa levels were decreased in the inactive group but not in the active group.

Conclusion: The authors concluded that decreasing the frequency of infliximab dosing is more effective than increasing the dose and
that serum TNFa levels can vary and not always correlate to clinical effectiveness.
Monitoring Plan:
Parameter Frequency

Continue CBC monitoring. Every 6 weeks. To check for anemia, monitor CKD.

Thyroid function test Every 6 weeks. (range = 4-8 weeks then


every 6 to 12 months per AACE
guidelines.)

Blood pressure, pulse. weight Every 6 weeks. At time of clinic visit. For presence/risk of orthostatic
Per JNC 8 guidelines goal hypotension.
BP= 140/90

Pain measurement using Every 12 weeks (per guidelines) At time of clinic visit. To measure the effectiveness
Routine Assessment of of the new dose of remicade.
Patient Index Data 3
(RAPID3).

Monitor for infections, check Every 6 weeks. At time of clinic visit


heart rate.
Drug Therapy Problem#2:
Indication for a drug but not prescribed properly. TSH levels are on the lower side while free T4 is high, this indicates likely
irregular or double dosing and in elderly patients a dose reduction can improve TSH function and be cardioprotective).

Rationale for intervention: Based on Endocrine research a dose reduction will improve TSH function and this has been shown to be
beneficial in older patients (ref=7,8,9).

Intervention to resolve drug therapy problem: for #2


Suggest to decrease levothyroxine dose to 75mcg to increase TSH function (20-25% decrease).
Pathophysiology of Hypothyroidism:
The thyroid gland produces thyroid hormones T4 (which gets converted to T3) and T3, the stimulation of the thyroid gland to
produce thyroid hormones is via a feedback mechanism involving the pituitary gland (TSH), hypothalamus (TRH) and the
levels of serum thyroid hormones.
In patients with hypothyroidism there is decreased production of T4 and hence the pituitary gland secretes more TSH.
Hypothyroidism can affect many processes including heart rate, cholesterol, infertility, menstrual problems and GI tract.

Pharmacology of Levothyroxine: Levothyroxine is a synthetic thyroid hormone of T4, it is the preferred drug as its
concentrations and effects are predictable.
Levothyroxine (T4) is converted to short acting and physiologically active T3, these hormones affect the growth of tissues,
bones, energy expenditure, cardiac effects and other processes.

Pharmacokinetics/dynamics of Levothyroxine: Levothyroxine is 99% bound to proteins. Oral absorption of Levothyroxine is


variable with best absorption seen on fasting. Absorption can be affected by food.
Levothyroxine (T4) is slowly metabolized mainly to T3 and also in the liver. Levothyroxine is mainly excreted via the kidneys
with a plasma t1/2=6-7 days in normal patients, 9-10 days in hypothyroid patients and 3-4 days in hyperthyroid patients.
The effects of exogenously supplied Levothyroxine may take 1-3 weeks to be observed.

Preparation/administration/stability/cost of Levothyroxine: Levothyroxine tablets are available under different strengths from 25
mcg to 200 mcg under names of 1-Levothyroxine tablets 2-Levothroid, 3-Levoxyl, 4-Unithroid, 5-Synthroid. Levothyroxine is
also available as an injection solution. Levothyroxine is inexpensive.
Scientific/Expert opinion: #1
7- Levothyroxine dose and risk of fractures in older adults: nested case-control study
Turner MR, Camacho X, Fischer HD, Austin PC, Rochon A et al. BMJ Apr 2011:342:d2238.

OBJECTIVE: The study looked at the association of levothyroxine supplementation and bone fractures in elderly patients
(70+yrs).

METHODS: This study was a nested case-controlled study on (231,511) patients aged 70 to 105 years old taking levothyroxine
supplementation for 5 years. The primary outcome was fracture of any kind. For each (fracture) case they were matched to 5
other controls (from the cohort study) who were still at risk for fractures.
The last prescription for levothyroxine from the date of fracture was used to classify patients as current users, recent past
users(not used in last 15-180 days) or remote users(not used in >180 days). Current users were compared to remote users for
fracture risks.

Results: 22,236 (10.4%) patients had a fracture. Current users were at a significantly higher risk for fractures v/s remote users
AOR (adjusted odds ratio) =1.88 (95%CI=1.71-2.05) similarly for recent past users 1.33 (95%CI=1.19-1.48).
Among current users a higher dose of levothyroxine was associated with higher fracture risks, similarly women had a higher
risk.

CONCLUSION: The authors concluded that current use of levothyroxine use was associated with increased risk of fractures in
older patients (>70years) in a dose increase manner. They also conclude that closer monitoring of levothyroxine doses in the
elderly is necessary to prevent overtreatment and subclinical hyperthyroidism.
Scientific/Expert opinion: #2
8- Low Serum Thyrotropin Concentrations as a Risk Factor for Atrial Fibrillation in Older Persons. CT. Sawin, A Geller, PA.
Wolf, AJ. Belanger, E. Baker, P. Bacharach, P. Wilson, EJ. Benjamin, and RB. D'Agostino. N Engl J Med nov 1994:331:1249-
1252.

Objective: To analyze the risk of atrial fibrillation (Afib) in older patients(60+) in relation to their serum thyrotropin levels over 10 years.

Methods: A prospective study over 10 years of 2007 patients was conducted. Serum thyrotropin levels were measured in and
patients were assigned to 4 groups of Low TSH (<0.1mU/L), slightly low TSH (0.1-0.4mU/L), normal TSH (>0.5-5mU/L) and
high TSH (>5mU/L). A multivariate analysis of the groups was done with the normal TSH group as the control. Afib was
diagnosed at the patient's biennial(2yrs) checkup during the 10 years.

Results: Afib developed in 192 patients of which


13 patients were in the low TSH group (cumulative incidence of afib after 10 years was 28%), also the age adjusted rate of afib
occurance was significantly higher in this group v/s normal group (p<0.005).
Also the relative risk of Afib was 3.1 (95% 1.7-5.5, p<0.0001) v/s normal group.
23 patients in the slightly low TSH group (cumulative incidence of afib after 10 years was 16%),
133 patients in the normal TSH group (cumulative incidence of afib after 10 years was 11%) and
23 patients in the high TSH group (cumulative incidence of afib after 10 years was 15%).

Conclusion: The authors concluded that low serum thyrotropin levels (<0.1mU/L) (subclinical hyperthyroidism) in patients
greater than 60 years was a risk factor to develop Afib.
Alternative Drug Therapy:
1- Etanercept (Enbrel) a soluble TNFa receptor antibody has slightly better effects in some studies v/s monoclonal antibodies
(dose is 50 mg SC weekly).
References:

1-Titration of infliximab treatment in rheumatoid arthritis patients based on response patterns. M. Flen, M. Creemers, P. van Riel.
Rheumatology. 16 June 2006:46:1:146-149.

2- TNFa therapy in rheumatoid arthritis: Correlation of TNF-a serum levels with clinical response and benefit from changing dose or frequency
of infliximab infusions. Edrees F, Misra N, Abdou I. Clinical and Experimental Rheumatology, July 2005, Vol:23:4:469-474.

3- Dose optimization of infliximab in patients with rheumatoid arthritis. R. Alten, F. Vanden bosch. Int J Rheumatology Disease. Jan
2014:17:1:5-18. Summary: Dose increase of infliximab shows a trend towards improvement in clinical outcomes.

4- A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks
can be effective: a Belgian prospective study. Durez P. F. Vanden bosch.Rheumatology. Apr 2005:44:4:465-468.

5- Recommendations of the French Society for Rheumatology regarding TNF alpha antagonist therapy in patients with rheumatoid arthritis. F.
Bruno, P. Thao et al. Joint bone spine: Dec 2007. Vol: 74:6:627-637.

6- Appropriate infliximab infusion dosage and monitoring: results of a panel meeting of rheumatologists, dermatologists and
gastroenterologists. H. Vries, M. Van Oijen et al. Br J Clinical Pharmacology. Jan 2011, 71:1: 7-19.

7-Levothyroxine dose and risk of fractures in older adults: nested case-control study
Turner MR, Camacho X, Fischer HD, Austin PC, Rochon A et al. BMJ Apr 2011:342:d2238.
References (continued):

8-Low Serum Thyrotropin Concentrations as a Risk Factor for Atrial Fibrillation in Older Persons. CT. Sawin, A Geller, PA. Wolf, AJ.
Belanger, E. Baker, P. Bacharach, P. Wilson, EJ. Benjamin, and RB. D'Agostino. N Engl J Med nov 1994:331:1249-1252.

9- Hoogendoorn H, DenHeijer M, VanDijk J, et al. Subclinical hyperthyroidism: to treat or not to treat? Postgrad Med Journal, 2004:80:394-
398.

10- Treatment of Hypothyroidism. WJ. HUESTON. Am Fam Physician. Nov 2001 15: 64:10:1717-1725.

11-American Thyroid Association Guideline for Treatment of Hypothyroidism by endocrineweb.

12-Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment
in patients with rheumatoid arthritis. Wolbink GJ, Voskuy AE, Lems WF, Groot E, Nurmohamed MT, Tak PP, Dijkmans BA, Aarden L. Ann
Rheum Dis. may 2005:64:5:704-707.

13- 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Singh et al. Arthritis Care & Research
2015.

14- CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS: COSPONSORED BY THE AMERICAN ASSOCIATION OF
CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN THYROID ASSOCIATION. JR Garber et al. Endocr Pract 2012:18:6:988-1028.