Rheumatoid Arthritis (RA) Review

Rheumatoid Arthritis (RA) Review

• RA is a symmetrical, inflammatory, peripheral polyarthritis with unknown etiology.
• Peak incidence is in women greater than men and symptoms start around midlife.
• RA can be caused by potential gene/environment interactions.
• Autoimmune factors play a role in RA development.
• Rheumatoid factors are present on tests (RA or RF test) in people with RA.
• Antibodies (IgG and IgM) form antigen/antibody complexes against self-antigens in blood and the synovial membrane.
• Joint pain and stiffness are clinical presentations of RA with pain being more intense in the morning.
• Limited joint movement can occur that causes pain and later fibrosis.
• RA may cause deformity, loss of function along with systemic manifestations.
• Systemic manifestations include fever, fatigue, weight loss, weakness, thinning of the skin, vasculitis, and subdermal nodules.

RA Drug Therapy: Goals & Classes

• Goals of RA therapy are to relieve symptoms, maintain joint function, and minimize systemic involvement.
• RA drug classes are NSAIDs, glucocorticoids, and DMARDs.
• NSAIDs are nonsteroidal anti-inflammatory drugs.
• DMARDs are disease-modifying antirheumatic drugs which can be nonbiologic, traditional or Biologic

Disease-Modifying Antirheumatic Drugs (DMARDS)

• DMARDS treat inflammatory diseases such as RA, SLE, psoriatic arthritis, ankylosing spondylitis, IBD, and some CA.
• DMARDS decrease joint damage and reduce risk for long-term disability.
• Non-biologic DMARDS generally work through immune system suppression and slow disease progression.
• Non-biologic DMARDS do not have a single MOA between classes.
• Biologics are used when patients fail non-biologic agents to target specific immune system cytokines.
• Biologics are targeted against specific immune system cytokines (tnf-a, iL-6), and other small molecule proteins.

DMARDS: Non-Biologic/Traditional

• Methotrexate (Rheumatrex or Trexall) is a first-line drug for RA; can be used as antineoplastic in chemotherapy.
• Methotrexate is an immunosuppressant with IM, SC, or PO routes.
• Methotrexate's MOA is immunosuppression via B & T lymphocyte actions and inhibiting DNA replication as a folic acid analog.
• Methotrexate is the fastest-acting DMARD, takes effect within 3-6 weeks, and is highly effective in 80% of patients.
• Methotrexate's toxicities include hepatic fibrosis, bone marrow suppression, GI ulceration, and pneumonia.
• Methotrexate requires liver, kidney tests, and CBC's performed
• Folic acid supplements should be given to decrease GI and hepatic toxicity.
• Methotrexate is contraindicated in pregnancy due to risk of fetal death and congenital deformities.
• Methotrexate risks include cardiovascular mortality and some cancers.
• Patients should drink 2-3 L of water per day to promote excretion and protect the kidneys while using Methotrexate.
• Other Non-biologic DMARDS are Sulfasalazine, Leflunomide (Arava), and Hydroxychloroquine.
• Sulfasalazine is used as an anti-inflammatory agent, to modulate the immune system, and treat IBD.
• Hydroxychloroquine (Plaquenil) is an anti-malarial with an unknown MOA that is used with methotrexate.
• All Non-biologic DMARDS carry risk of serious infection.

Biologic DMARDS and Etanercept (Enbrel)

• Biologic DMARDS target specific components of the inflammatory process, usually combined with methotrexate.
• Most Biologic DMARDS used in RA are targeting tumor necrosis factor (TNF).
• Biologic DMARDS pose risk of serious infection and cancer, are created using recombinant DNA technology, and are expensive.
• Example Biologic DMARDS that inhibit Tumor Necrosis Factor (TNF) are Etanercept [Enbrel], Adalimumab [Humira], Certolizumab pegol [Cimzia], Golimumab [Simponi Aria], and Infliximab [Remicade].
• Etanercept (Enbrel) is used when patients do not respond to methotrexate; may be given in combo w/methotrexate as SC injection once weekly.
• Etanercept suppresses inflammation by inactivating TNFa; it binds to TNF, preventing interaction with cell receptors.
• Etanercept treats moderate to severe RA symptoms, reduces disease progression, and can treat psoriasis.
• Mild adverse effects of Etanercept are injection site reactions, headache, rhinitis, cough, and abdominal pain.
• Serious adverse effects the drug can cause serious infections (including fungal, TB, latent hepatitis B) and heart failure, hematologic disorders, liver injury and CNS demyelinating disorders.
• Live virus immunizations should be avoided during Entanercept use; inactivation of TNF increases risk for acquiring or transmitting virus.
• Immunosuppressants (glucocorticoids, etc) should be used with caution.
• Etanercept is administered via weekly subcutaneous injection.

Gout and Pharmacology for Gout

• Gout is caused by hyperuricemia: uric acid levels >7mg/dL in males, >6mg/dL in females.
• Hyperuricemia is from excessive production of uric acid and/or impaired renal excretion; joint pain is caused by uric acid crystal deposits.
• Deposits in kidneys from hyperuricemia cause renal damage, and is more common in men.
• The MTP joint is most often affected by gout.
• Gout is associated with, "Rich man's disease" with contributing factors like alcohol, high-fructose drinks, meat, and seafood.
• Short term treatment goals are relief of acute gout attack with NSAIDS and Colchicine.
• Colchicine's onset is 12 hours with an unknown MOA.
• Long term treatment goals are to reduce blood levels of uric acid: urate-lowering therapies using Xanthine oxidase inhibitors (Allopurinol).
• Additional medications include Uricosuric agents (Probenecid) & Recombinant uric acid oxidase (Pegloticase).
• Colchecine is a NSAID specific to gout, some patients experience high levels of GI toxicity (25% of pts).
• The use of Colchecine can case Myelosuppression
• When using Colchecine avoid Statins and PGP & CYP3A4 inhibitors such as grapefruit juice
• Caution should be used in renal/liver and GI populations when administering this medication
• All agents for urate-lowering therapy can cause an initial gout flare which can be decreased with NSAIDS.
• Allopurinol (Zyloprim) is a xanthine oxidase inhibitor which reduces blood uric acid levels, prevents tophi and decreases tophi size.
• Allopurinol (Zyloprim) can be used to treat hyperuricemia secondary to chemotherapy and lowers risk of Urate kidney stones.
• Allopurinol (Zyloprim) adverse effects include rare but potentially fatal hypersensitivity syndrome and rash with flat or raised lesions.
• Mild side effects for Allopurinol can be GI symptoms and neurologic effects (drowsiness, headache, metallic taste)
• Probenecid (generic only) acts on renal tubules to inhibit reabsorption of uric acid, increasing excretion of uric acid and preventing tophi.
• Pegloticase (Krystexxa) is an IV therapy for those who have not responded to allopurinol or probenecid.
• Pegloticase (Krystexxa) MOA is enzymatic conversion of uric acid to inactive, water-soluble product
• Pegloticase (Krystexxa) carries a high risk of anaphylaxis (6.5%) and transfusion reactions (26-41%).

Osteoporosis: Prevention, pathophysiology, and medications

• Osteoporosis can be prevented with discussion of pharmacologic options.
• Pharmacologic agents affect the bone remodeling process with drugs having mechanism of action route of administration and side effects
• A thin postmenopausal female is most at risk for osteoporosis.
• Osteoporosis develops whenever remodeling cycle and the process of bone resorption and formation is disrupted.
• Osteoclastic activity increases > osteoblastic activity.
• Aging + loss of sex hormones (estrogen) leads to bone loss in people with Osteoporosis.
• Osteoblasts are needed to create a balance but are fragile which increases the risk of fractures
• Estrogen is anti-apoptotic on osteoblasts and pro-poptotic on osteoclasts.
• Osteoprogenitor cells form into undifferentiated cells and differentiate into adipocytes, fibroblasts, muscle cells, osteoblasts.
• Osteoblasts form new bone.
• Osteocytes are mature bone cells that are housed within calcified bony matrix, responsible for synthesis & degradation of bone matrix.
• Osteoclasts are responsible for bone resorption, secreting lysosomal enzymes to digest matrix proteins & release calcium and phosphate.
• Calcium, parathyroid hormone(PTH), Vitamin D, and Calcitonin is critical for bone health.
• Selective estrogen receptor modulators (SERMS), Bisphosphonates, Calcitonin,, Calcium, Parathyroid Hormone (PTH), and Denosumab are bone mineralization pharmacology treatments.
• Osteoporosis Medications can either be antiresorptive or anabolic to help to form new bone.
• Antiresorptive osteoporosis medications are Bisphosphonates [Alendronate, Ibandronate, Risedronate, Zoledronic acid, Calcitonin -salmon nasal spray [Miacalcin, Fortical], Estrogen [Premarin], Estrogen Agonist/Antagonist (SERM): Raloxifene [Evista], Denosumab Injection [Prolia, Xgeva],
• Anabolic osteoporosis medications are Parathyroid Hormone [Teriparatide] and Romosozumab (2020) mAb for your information only.
• Romosozumab (2020) mAb increases osteoblast activity and Decreases osteoclast activity.
• Primary prevention of osteoporosis comes from adequate dietary Ca++.
• To help with calcium intake people need to intake > 1000 mg/day or Females > 50, males >71: > 1200 mg/day
• Vitamin D intake needs to be between 600-800 IU/day
• 3 oz of canned salmon provides the most calcium out of 1 cup of carrots, 3 oz. canned salmon, 1 cup chopped chicken breast, or 1 plain baked potato
• Hormone Therapy: Estrogen indirectly suppresses osteoclast proliferation which slows bone resorption
• This therapy is also approved for use in women post menopause
• This therapy does reduce the risk of fractures up to 24%
• There is a high risk for breast CA, MI, stroke when using this medication that requires a discussion with the patient so they know benefits outweigh the risk of the medication
• Raloxifene (Evista) AKA: Selective estrogen receptor modulator (SERM) and Structurally similar to estrogen and binds to estrogen receptors
• Raloxifene (Evista) reduces bone turnover and improves BMD.
• Raloxifene (Evista) differs from estrogen which and comes with protection against breast cancer.
• Raloxifene (Evista) comes with black box warning with risks for DVT, PE, and stroke.
• Raloxifene (Evista) are typically not prescribed to pregnant patients because it can cause fetal harm
• Bisphosphonates drugs Alendronate [Fosamax], Risedronate [Actonel], Ibandronate [Boniva], etc are available to decrease the bone density
• Bisphosphonates MOA is that it Structural analogs of pyrophosphate which becomes incorporated into bone and decrease bone resorption by inhibiting osteoclast activity
• Bisphosphonates dosing: PO/IV schedule and route vary by drug. Range from daily-yearly (IV). Patient must always Check schedule!
• Take in morning on empty stomach-water only (low bioavailability) and Must wait 30-60 minutes before eating
• Patients must remain upright~30-60 minutes-risk for oral esophagitis
• When administering this medication you must be very careful and educate the pt
• Bisphosphonates have have risks for : Esophagitis ,Musculoskeletal pain,Ocular inflammation, Jaw osteonecrosis patients on IV bisphosphonates and using IV Zoledronate
• Denosumab is a human monoclonal antibody of RANKL inhibitor that Binds to receptor activator of nuclear factor kappa B ligand (RANKL)
• Denosumab prevents RANKL from activating RANK on osteoclast surface and prevents osteoclast formation, function, survival
• Denosumab is Used in men and women with patients receiving subcutaneous injections every 6 months and with a supplement of Ca++ and Vit. D
• Denosumab has a potential for Adverse Effects : Back & MS pain, Pain in extremities , Hypercholesterolemia and increased bladder infections.
• Denosumab has a potential Risk for osteonecrosis of Jaw
• Calcitonin inhibits osteoclast activity and inhibits tubular resorption & increases calcium excretion by kidneys leading to decreases bone turnover
• Calcitonin not used for prevention but may be used for post-menopausal tx or be used as a 2nd line to therapy from bisphonates
• Calcitonin may be used as a medication for Pagets disease for management of osteoporotic pain

Parathyroid

• PTH: Teriperitide Injection: Forteo is known as the only that increases bone formation
• PTH: Teriperitide Injection: Forteo is typically only used in women with osteoporosis and men at high risk for fracture
• There may be bone resorption and deposition
• The net effects are based on drug administration
• This medications has the patient preform Dailey SC injections to to cause transient increases in PTH= more bone deposition by osteoblasts
• Continues IV of this medication cause steady increased PTH and bone resorption by osteoclasts
• There is a risk for side effects and symptoms : leg cramps, nausea, dizziness
• Contraindicated patients are those with a risk for osteosarcoma or who have Paget's or H/O skeletal malignancy