2. Learning objectives
Upon completion of the chapter, you will be able to:
Explain the pathophysiologic mechanisms for rheumatoid arthritis.
List the symptoms associated with rheumatoid arthritis (RA).
List the extra-articular manifestations of RA.
List the laboratory tests used in diagnosing RA.
Components of non-drug approaches to assist in the management of RA.
Create a stepwise plan for treatment of RA in a patient who does not
respond to therapy.
Design a therapeutic & monitoring plan to treat RA.
2
3. Mini case
A. A, a 37 year-old woman with a 5-year history of rheumatoid arthritis who
presented with fatigue and dyspnea from Jimma. One month before her admission
to JUMC , she developed pleuritic chest pain and was treated by her primary care
provider for “bronchitis” with Amoxicillin. Over the next five days her pain
worsened and she became short of breath. She was admitted to Shenen Gibe
hospital , where she was found to be in new-onset atrial fibrillation with an
elevated troponin level of 4.4 ng/ml. Echo showed a small pericardial effusion.
Past Medical History: HTN, Gastritis.
What other investigation should be done?
Complication from RA?
How can we treat optimally?? DOC, safety concern!!!
Any drug interaction and pharmaceutical care revision??
Monitor and evaluate??
3
5. Introduction: RA
Most common systemic inflammatory disease characterized by
symmetrical joint involvement
Chronic, progressive inflammatory disorder of unknown etiology.
x-zed by poly-articular symmetric joint involvement and systemic
manifestations.
5
6. Epidemiology
Prevalence in US: 1%, 1-2% of the world’s population.
Can occur at any age, with increasing prevalence up to the 7th
decade of life.
More common in women (3x)
From ages 15 to 45 yrs; women :men6:1; otherwise equal.
6
7. Etiology
Cause of RA is unknown.
Genetic: account for 50% of the risk.
Environmental, hormonal, immunologic, and infectious factors may
play significant roles.
7
HLA-DR-4: present peptide to T cells
8. Pathophysiology
It results from a complex interaction between genes and environment
breakdown of immune tolerance and synovial inflammation.
Given the heterogeneous response to therapy, RA in not just a single
disease.
The initiation of RA is a combination of pre-determined (genetic) and
stochastic (random) events.
Susceptibility to RA is clearly defined by a pattern of inherited genes,
with the HLA major histocompatability genes as the most important.
However, scores of minor genes : cytokine promoters, T cell signaling
genes, and many others, contribute to susceptibility and severity.
8
Genetic or infectious antigen?!!
9. Immune system: complex network of checks and balances
designed to discriminate self from non-self (foreign) tissues.
It helps rid the body of infectious agents, tumor cells, and products
associated with the breakdown of cells.
In RA, this system no longer can differentiate self from non-self
tissues attacks the synovial tissue and other connective tissues.
9
Cont’d…
10. The characteristics of a synovium affected by RA are:
a) Presence of a thickened, inflamed membrane lining called pannus.
b) Development of new blood vessels; and
c) Influx of inflammatory cells in the synovial fluid, predominantly T
lymphocytes.
The pathogenesis of RA is driven by T-lymphocytes, but the initial catalyst
causing this response is unknown.
Components of the immune system and their involvement:
T-lymphocytes, cytokines, and B-lymphocytes
10
Cont’d…
11. T-Lymphocytes
Development and activation of T lymphocytes!!
Maintain protection from infection without causing harm to the
host.
Activation of mature T lymphocytes requires two signals.
Presentation of an antigen by APC to the T-lymphocyte
receptor.
A ligand-receptor complex (i.e., CD80/CD86) on antigen-
presenting cells binds to CD28 receptors on T-lymphocytes.
activation of inflammatory cascade.
11
APC: antigen-presenting cells
12. Activation of T lymphocytes
Stimulates the release of macrophages or monocytes,
release of inflammatory cytokines
Activates osteoclasts
Activates the release of matrix metalloproteinases or enzymes
responsible for the degradation of connective tissue.
Stimulates B lymphocytes and the production of antibodies.
12
13. Cytokines
Are proteins secreted by cells (serve as intercellular mediators).
Can be
a) Pro-inflammatory: IL-1, IL-6, IL-17,TNF-α (high concentrations in
synovial fluid)
b) Anti-inflammatory: IL-4, IL-10, and IL-1 receptor antagonist
Imbalance inflammation and joint destruction.
Pro-inflammatory cytokines activation of other cytokines and
adhesion molecules recruitment of lymphocytes to the site of
inflammation.
13
15. B Lymphocytes
Serve as
APCs to T lymphocytes.
Produce pro-inflammatory cytokines and antibodies.
Antibodies of significance: rheumatoid factors (RFs) and antibodies against cyclic
citrullinated peptide (CCP).
RFs are not present in all patients with RA
Its presence indicate: disease severity, likelihood of extra-articular
manifestations, and increased mortality!!
CCPs: produced early in the course of disease.
High levels of anti-CCP antibodies: indicative of aggressive disease
and a greater likelihood of poor outcomes.
15
25. Dx of Juvenile Idiopathic Arthritis (JIA)
Age <16 years at disease onset
Arthritis in one or more joints for more than 6 weeks
Exclusion of other types of arthritis.
25
26. Systemic (10%):
Girls : boys ; 1:1
X-tic fever spikes twice daily
(>38.3°C)
Presence of a pale, pink,
transient rash.
The peak onset :1 and 6
years.
Polyarticular (40%):
Girls >boys (3:1)
Arthritis of ≥ 5 joints.
Resembles adult RA
Pauciarticular (50%):
Girls > >boys (5:1).
Uveitis is more likely
Arthritis of ≤ 4 joints.
Categorized:
Early onset (more in girls)
Late onset (more in boys)
26
Types of JIA
27. Poor prognosis indicators
The most clinically important features associated with poor long-
term outcomes:
Functional limitation (Health Assessment Questionnaire [HAQ] score)
Extra-articular disease
Positive rheumatoid factor
Positive anti-CCP antibodies, and/or
Bony erosions by radiography.
27
28. Extra-articular Involvement
Rheumatoid Nodules
Occur in 20% of patients with RA.
Commonly on the extensor surfaces of the
elbows, forearms, and hands.
Also in lung or pleural lining, meninges
Vasculitis: invasion of blood vessel walls by
inflammatory cells
In patients with long-standing RA
Results in an obliteration of the vessel
infarction of tissue distal to the area (ends of
the fingers or toes)
28
29. Pulmonary Complications
Pleural effusions, Interstitial pneumonitis and arteritis, nodules
Smoking increase the risk.
Cardiac Involvement
Pericarditis accumulation of fluid.
Aggressive management of systemic inflammation and traditional
cardiovascular risk factors (e.g., blood pressure, cholesterol, tobacco use)
Felty's Syndrome: splenomegaly + neutropenia
Also thrombocytopenia
More susceptible to infection
29
30. Malignancy
Increased risk of developing lymphoproliferative
malignancy (e.g., lymphoma, leukemia, and
multiple myeloma) and lung cancer.
Osteoporosis
Increased osteoclast activity; Inhibit osteoblast
activity.
Renal involvement
Rare (associated NSAIDs, gold salts, and
penicillamine).
30
31. Treatment
Desired Outcomes
Reduce or eliminate pain,
Protect articular structures,
Control systemic complications,
Prevent loss of joint function,
Improve or maintain quality of life.
Maintaining normal growth, development, & activity level(for
JIA/JRA).
31
32. General Approach to Treatment
Early dx and early aggressive Rx necessary (reduce disease
progression and prevent joint damage).
Aggressive treatment: use of 1 or more DMARDs at effective doses.
Disease severity and presence of poor prognostic features
DMARD should be started within the first 3 months of symptom onset.
Options:
NSAIDs
Glucocorticoids
Non-biologic DMARDs,
Biologic DMARDs.
32
DMARDs: disease-modifying anti-rheumatic drugs
Treat based on
Activity level of the patient’s disease,
Presence or absence of poor prognostic
features,
Duration of disease activity (early vs.
established).
Early introduction of DMARDs results in a more favorable outcome
33. Non-pharmacologic Therapy
Rest: alleviation of pain
Occupational therapy, physical
therapy: skills and exercises
necessary to increase or maintain
mobility
Use of assistive devices: Canes,
walkers, and splints
Weight reduction:
Surgery :
33
34. Early RA with low disease activity: non-biologic DMARD monotherapy
(initial Rx)
Hydroxychloroquine, minocycline, leflunomide, methotrexate, or
sulfasalazine.
Moderate/high disease activity but without poor prognostic features:
DMARD monotherapy or methotrexate+ hydroxychloroquine (initial
Rx).
Moderate/high disease activity and evidence of poor prognostic
features:
Combination: methotrexate +hydroxychloroquine, methotrexate+
sulfasalazine or methotrexate+ sulfasalazine+ hydroxychloroquine.
Alternative: started on anti-TNF therapy with or without
methotrexate.
34
Early RA Rx
35. 35
Recommendations for the treatment of early RA (disease duration less than 6 months)
bCombination DMARD therapy:
methotrexate + leflunomide,
methotrexate + hydroxychloroquine,
methotrexate + sulfasalazine,
sulfasalazine + hydroxychloroquine.
Triple DMARD therapy:
methotrexate + hydroxychloroquine
+ sulfasalazine.
36. Biologic DMARDs : Consider in patients with established RA following
inadequate response to non-biologic.
Switch: in a patient who experiences an inadequate response or
adverse event.
Combination is mandatory in most of cases.
36
Established RA Rx
37. 37
Recommendations for the treatment of
established RA (disease duration 6 month or
longer)
bCombination DMARD therapy
methotrexate + leflunomide,
methotrexate + hydroxychloroquine,
methotrexate + sulfasalazine,
sulfasalazine + hydroxychloroquine.
Triple DMARD therapy:
methotrexate + hydroxychloroquine +
sulfasalazine.
cReassess after 3 months of adequate
therapy.
dReassess after 6 months of adequate
therapy
38. 38
Poor prognosis: limitation in function, extra-articular findings (rheumatoid nodules, vasculitis, Felty
syndrome, Sjogren syndrome, rheumatoid lung findings, erosions on radiograph).
Algorithm for treatment of RA using non-biologic DMARDs
40. NSAIDS
Analgesic and anti-inflammatory benefits for joint pain and swelling.
Don’t prevent joint damage or change the underlying disease.
As “bridge therapy” to provide symptomatic relief until the therapeutic
effect of the DMARD is observed.
If a patient does not receive relief from one NSAID, it is acceptable to
try a second one (interpatient variability in response)
40
NSAIDs and/or corticosteroids may be used for symptomatic relief
provide relatively rapid improvement in symptoms compared with DMARDs (weeks to
months)
41. Adverse event of NSAIDS:
GI ulcers or hemorrhage, fluid retention, exacerbation of existing
hypertension, and decreased renal function
Factors that place a patient at a higher risk of GI-related adverse reactions
include:
History of PUD.
High doses of NSAIDs.
Concomitant use of other medications with an increased risk of GI
hemorrhage or ulcers (e.g., anticoagulants, corticosteroids, use of multiple
NSAIDs)
Age greater than 75 years
41
42. Increased risk of NSAID-induced adverse reactions: use gastro-protection:
PPI: preferred, greater acid suppression, prevention of both gastric and
duodenal ulcers, and a tolerable adverse-effect profile
Misoprostol: effective in reducing the occurrence of gastric and
duodenal ulcers (but, diarrhea limit its use)
H2RA: prevent duodenal ulcers (but not gastric ulcers)
NSAIDs may accentuate the increased risk of CV events inherent in
patients with RA.
Increases in blood pressure and fluid retention may exacerbate existing
CV disease.
42
43. 43
Dosage Regimens for Nonsteroidal Anti-inflammatory Drugs
Drug Adult Children Dosing Schedule
Aspirin 2.6–5.2 g 60–100 mg/kg 4x daily
Celecoxib 200–400 mg – Daily to twice daily
Diclofenac 150–200 mg 3-4x daily; Extended release
twice daily
Diflunisal 0.5–1.5 g – Twice daily
Etodolac 0.2–1.2 g (max. 20
mg/kg)
– Twice daily to 4 times daily
Fenoprofen 0.9–3.0 g – Four times daily
Flurbiprofen 200–300 mg – 2-4x daily
Ibuprofen 1.2–3.2 g 20–40 mg/kg 3-4x daily
Indomethacin 50–200 mg 2–4 mg/kg
(max. 200 mg)
T2-4x daily
Extended release daily
Meclofenamate 200–400 mg – 3-4x per day
Meloxicam 7.5–15 mg – Daily
Nabumetone 1–2 g – Daily to twice daily
Naproxen 0.5–1.0 g 10 mg/kg 2x Extended release–daily
Naproxen sodium 0.55–1.1 g – Twice daily
Nonacetylated salicylates 1.2–4.8 g – 2-6x per day
Oxaprozin 0.6–1.8 g (max. 26
mg/kg)
– 1- 3 x a day
Piroxicam 10–20 mg – Daily
Sulindac 300–400 mg – Twice daily
Tolmetin 0.6–1.8 g 15–30 mg/kg Twice daily to 4 times daily
44. Corticosteroids
Anti-inflammatory and immunosuppressive properties.
Interfere with antigen presentation to T lymphocytes,
Inhibit prostaglandin and leukotriene synthesis,
Inhibit neutrophil and monocyte superoxide radical generation.
Impair cell migration redistribution of monocytes, lymphocytes, and
neutrophils blunting the inflammatory and autoimmune responses.
Used in bridging therapy, continuous low-dose therapy, and short-
term, high-dose bursts to control flares.
44
Control pain and synovitis
45. Patients with difficult-to-control disease: low-dose, long-term corticosteroid(control
their symptoms).
Alternate-day dosing not recommended (due to flares).
High-dose corticosteroid bursts: to suppress disease flares.
Sustained for several days until symptoms are controlled taper to the
lowest effective dose.
Intramuscular steroids: in patients with adherence problems for short-term
therapy.
Long-acting depot steroids:
Provides the patient with 2 to 6 weeks of symptomatic control.
Provides a physiologic taper, avoiding withdrawal reaction
Triamcinolone acetonide, triamcinolone hexacetonide, and
methylprednisolone acetate.
45
46. IV steroids: Patient with large amounts of drug during a steroid burst to
control severe symptoms.
Intra-articular depot forms steroids: treat synovitis and pain when a
small number of joints are affected.
Fewest number of systemic adverse effects (preferred to IV/IM)
If effective, may be repeated every 3 months
No one joint should be injected more than 2 to 3 times per year (joint
destruction and atrophy of tendons).
Side effects: Bone loss, Cushing's syndrome, PUD/gastritis, hypertension,
weight gain, infection, mood changes, cataracts, dyslipidemia, and
hyperglycemia, skin atrophy
46
47. DMARDs
Non-biologic and biologic
Mainstay of RA treatment (modify the disease process and prevent or
reduce joint damage).
Initial choice depends on: disease severity, patient characteristics (i.e.,
comorbidities, likelihood of adherence), cost, and clinician experience with
the medication.
Methotrexate alone or in combination: initial treatment.
Early, mild disease: monotherapy of sulfasalazine, leflunomide or
hydroxychloroquine.
Agents: azathioprine, penicillamine, gold salts, and rarely used
today(toxicity and reduced efficacy).
47
48. Non-biologic DMARDs
Inhibit of dihydrofolate reductase, which causes the inhibition of purines and
thymidylic acid and by inhibiting the production of certain cytokines.
Once-weekly doses within 3 months of dx increased steadily until the patient
has symptomatic improvement or a maximum dose of 20 mg/week is reached.
Concomitant folic acid necessary : to prevent (e.g., stomatitis, diarrhea, nausea,
alopecia, myelosuppression, and elevations in liver function tests)
Effect may be seen early as 2 to 3 weeks after starting therapy; maximal
response in 3 to 6 months
48
Methotrexate Oral or IM: 7.5–15 mg q wk 5 -15 mg/m2 q wk in JIA
If dose >15mg give parenteral, decreased BA
of oral, due to saturable kinetics
49. Methotrexate: concern!!!
Contraindication
Pregnant and nursing women, DC 3 months prior to attempting conception.
Chronic liver disease, immunodeficiency,
Pleural or peritoneal effusions,
Leukopenia, thrombocytopenia, preexisting blood disorders,
CrCL < 40 mL/min.
Side effects:
Stomatitis (3% to 10%) D, V, N(10%, thrombocytopenia (1% to 3%),Leukopenia
Pulmonary fibrosis, pneumonitis ( rare, severe)
hepatotoxicity (15%), cirrhosis (rare)
49
50. Leflunomide
Inhibits pyrimidine synthesis decrease in lymphocyte proliferation and
modulation of inflammation.
Inhibits Dihydroorotate dehydrogenase** inhibits the T-lymphocyte
response
LD 100 mg daily for 3 days, followed by a MD of 20 mg daily
Long elimination t1/2 (14–16 days); so take time to reach steady
state.
Use low dose if GI intolerance, complain of hair loss.
Side effects: hepatotoxicity, bone marrow toxicity
Teratogenic (use contraceptive)
50
** Enzyme supplies T lymphocytes with the necessary components to respond to cytokine stimulation
51. If conception is desired, leflunomide must be discontinued.
Because leflunomide undergoes enterohepatic circulation, the drug takes
many months to drop to a plasma concentration.
Use cholestyramine: 240 mg/kg/day
To rapidly clear the drug from plasma.
In the event of severe toxicity.
51
UMP: uridine monophosphate
52. Hydroxychloroquine
Exact MOA unknown
Immunomodulatory activity in T helper 17 (Th17) cytokines.
Diminish the formation of peptide-MHC protein complexes required to stimulate
CD4+ T cells in down-regulation of the immune response against auto
antigenic peptides.
Its onset delayed up to 6 weeks (wait 6 months of therapy to say
therapeutic failure).
Advantage: lack of myelosuppressive, hepatic, and renal toxicities
Side effects: N, V, D, accommodation defects, benign corneal deposits, blurred
vision, rash, alopecia, and increased skin pigmentation; headache, vertigo, and
insomnia
52
53. Sulfasalazine
A prodrug (cleaved in to sulfapyridine and 5-aminosalicylic acid) by
bacteria in the colon (azoreductase)
Sulfapyridine moiety: responsible for its antirheumatic properties.
Antirheumatic effects should be seen in 2 months.
GI adverse effects (N, V, D, and anorexia) limit its use.
Start with low doses and titrating gradually to higher doses,
Dividing the dose more evenly throughout the day, or
Use enteric-coated preparations.
53
In older than 6 years is 30 to 50 mg/kg/day in 2 doses
54. Other side effects of sulfasalazine:
Rash, urticaria, and serum sickness-like reactions: use
antihistamines/corticosteroids.
Hypersensitivity reaction occurs: stop immediately and another DMARD
substituted.
Leukopenia, alopecia, stomatitis, and elevated hepatic enzymes.
Urine and skin to turn a yellow-orange color (adherence??)
Its absorption can be decreased,
if antibiotics used (effect on colonic bacteria).
Binds iron supplements
Potentiate warfarin's effects by displacing it from protein-binding sites.
54
55. Biologic DMARDs
Genetically engineered protein molecules that block the pro-
inflammatory cytokines
TNF-α (infliximab, etanercept, adalimumab, golimumab, and
certolizumab),
IL-1 (anakinra), & IL-6 (tocilizumab),
Deplete peripheral B cells (rituximab), or
Bind to CD80/86 on T cells to prevent the co-stimulation
needed to fully activate T cells (abatacept).
55
56. Selecting a Biologic DMARD
The risk of infection in patients treated with biologic DMARDs must be considered
when selecting and monitoring therapy.
Use of TNF-α antagonists in patients with a history of tuberculosis exposure.
Reactivated infection of latent TB!!??
Initiated after at least 1 month of anti-tuberculosis treatment.
Patients with untreated hepatitis B should not receive them.
Should not be initiated during an acute, serious infection and should be discontinued
temporarily during times of infection
Cost consideration
Rituximab should be discontinued 1 year prior to planned conception.
Abatacept should be discontinued 10 weeks prior to planned conception.
56
![Musculoskeletal disorders therapeutics
By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
02, January, 2017
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609
Chapter 1
Rheumatoid Arthritis
1](https://image.slidesharecdn.com/3efca013-5518-4188-a4ee-e1924dcf4663-170104083238/85/rheumatoid-arthritis-1-320.jpg)
