Arthritis - Therapeutics II

Exam V

Where does RA vs OA effect the joints of the hand?

• RA is more likely to affect the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints

• OA is more likely to affect the distal interphalangeal (DIP) and Carbometacarpal phalangeal (CMC) joints.

Describe Systemic Lupus Erythmatosus

• Heterogenous autoimmune disorder which can affect any organ system; disease course is characterized by remission and relapses. There are 4 types of lupus erythmatosus:

  • Systemic Lupus Eryhtematosus (Most common)

  • Discoid (skin)

  • Drug-induced

  • Combination

Describe Scleroderma

• Autoimmune disease of connective tissue characterized by excessive collagen deposition in the skin and internal organs. Scleroderma presents as 2 distinct clinical entities:

  • Diffuse or Generalized form

  • Limited form called the CREST variant

    • Calcinosi

    • Raynaud’s phenomenon

    • Esophageal dysmotilities

    • Sclerodactyly

    • Telangiectasias

Define Seronegative Spondyloarthropathies

Spine disorders. Becuase there is an absence of rheumatoid factor (RF), these disorders are referred to as seronegative spondyloarthropathies

Define Ankylosing spondylitis

Inflammatory erosion of the sites where tendons and ligaments attach to bone which result in posterior fusion (ankylosing) of the spine. Ocassionally, large synovial joints (hips, knees, shoulders) may be involved. The underlying mech appears to be autoimmune.

Define Reactive Anthropathies

Sterile inflammatory joint disorders that are distant in time and place from the inciting infective process

Define Psoriatic arthritis

Heterogenous inflammatory arthritis associated with psoriasis. It is usually, but not always seronegative (RF negative). It may involve appendicular joints, axial joints, or both

Define Enteropathic arthritis

Arthritis assciated with inflammatory bowel disease (ulcerative colitis, chron’s)

Define Crystal-Induced Arthropathies

Metabolic bone and joint disorders which affect the joints; gout and pseudogout are common forms

Define Polymyalgia Rheumatica

Inflammatory condition of unknown origin characterized by aching and morning stiffness in the shoulders and pelvic areas

Describe Osteoarthritis. Where does it affect?

Degenerative Joint Disease—degeneration of cartilage that reflects failure of the chondrocyte to maintain proper balance between formation and destruction

• Variable degrees of LOCAL inflammation; no systemic symptoms

• Affects weight-bearing joints:

  • Pain

  • Limitation of movement

  • Disability

  • Decreased QOL

Describe the Pathophysiology of Osteoarthritis

• Initial damage to articular cartilage

  • Increase in chondrocyte activity

  • Destruction of the major structural components of the articular cartilage

• Degradation of Cartilage

  • Joint space narrowing

  • Osteophyte (new bone) at joint margins

Describe the Clinical Presentation of OA

Symptoms:

• Joint pain, often asymemtrical

• Joint stiffness at rest (<30min) which resolves with motion

  • Gel Phenomenon—thickening of synovial fluid when a joint is at rest for a prolonged period

Signs:

• Crepitus — cracking of joints upon movement

• Decreased range of motion

• Joint enlargement

• Heberden’s nodes

• Bouchard’s nodes

• Deformity (late stage)

List Joints involved in OA

• Knees

• Hips

• Hands

  • Interphalangeal joints

  • First carpometacarpal joints

• Spine

  • Lower lumbar spine

  • Cervical spine

How is Joint OA Diagnosed?

May be diagnosed confidently on clinical grounds alone if the following are present:

• Persistent usage-related joint pain in one or few joints

• Age ≥ 45years

• Morning stiffness ≤30min

How is Hip OA Diagnosed?

Hip Pain + 2 of the following:

• Erythrocyte sedimentation rate (ESR) <20mm/hour [inflammation]

• Osteophytes on radiography

• Joint space narrowing on radiography

How is Knee OA Diagnosed?

Knee pain, Osteophytes on Radiography, and at least on of the following:

• Age > 50yo

• Morning Stiffness < 30min

• Crepitus

• Bony enlargement or tenderness

• Palpable warmth

Describe nonpharm therapy of OA

• Education

• Diet

• Exercise

  • Land-based exercise

  • Aquatic exercise

  • Mind-body exercise (Tai Chi, yoga)

• Cognitive behavioral therapy

• Orthotics (Devices that support joint movement)

• Surgery

  • Joint replacement

  • Arthrodesis

  • Osteotomy (removal of part of a bone)

When is Topical NSAID therapy preferred in OA?

Knee and Hand OA involving 2 or fewer joints

When is Oral NSAID therapy preferred in OA?

Hip OA, OA involving more than 2 joints, and/or those with inadequate response to topical therapy

How long should NSAID therapy be used before reassessment?

2-3 week trial is needed for both topical and systemic NSAIDs

What is the most common AE associated with Systemic NSAIDs

Gastroduodenal toxicity

• Minor complaints are common and concomitant food or milk minimizes risk

  • Nausea, dyspepsia, anorexia, flatulence, diarrhea

• Peptic ulcer disease is less common

What are risk factors for NSAID-induced Gastroduodenal toxicity?

• History of an uncomplicated ulcer

• Age > 65 years

• High-dose NSAID

• Concurrent use (1 point each)

  • Aspirin

  • Systemic corticosteroids

  • Anticoagulants

When should Standard-dose PPI therapy be started to prevent Gastroduodenal toxicity?

• High Risk: complicated ulcer or ≥3 risk factors (Start PPI)

• Moderate Risk: 2 risk factors (Start PPI)

• Low risk: 0-1 risk factors (no need for PPI)

Describe H2RA use in prevention of Gastroduodenal toxicity?

They really only protect against NSAID-induced duodenal ulcers, but Gastric Ulcers are more common.

Describe Systemic NSAID Therapy Toxicity

• Myocardial Infarction, cerebrovascular accident

  • COX-2 selectivity increases risk

    • Rofecoxib—clear risk, withdrawn from market

    • Celecoxib—evidence for risk with higher doses (>400mg/d)

• Hemorrhage — increases with COX-1 selectivity

• Fluid retention

  • Edema

  • Hypertension

  • Heart Failure

Describe risk factors for Kidney Toxicity with NSAID therapy

• Intravascular volume depletion

• Chronic kidney disease

• Age > 65years

• Concomitant nephrotoxins

  • ACE/ARB

  • TMP/SMX (Bactrim)

  • Loop diuretics

  • Aminoglycosides

Describe the use of Capsaicin in OA

• Recommended for hand or knee OA involving 2 joints or less

• Available for purchase without a prescription as a topical

• AEs generally subside after repeated use

  • Burning, stinging, erythema at application site

• Patient instructions

  • Must be used regularly (not PRN) (Applied 2-4x/d)

  • Takes 2wks to work

  • Wash hands after application

Describe the use of Duloxetine (Cymbalta) in OA

SNRI

• Only recommended for Knee OA

• Reduction in pain occurs 4 weeks after initiation

• Preferred if neuropathic pain and/or depression also present

• AEs:

  • Nausea

  • Vomiting

  • Constipation

List the Intraarticular Corticosteroids. Describe their therapy.

Triamcinolone Acetonide or ER

Methylprednisolone acetate

• Pharmacokinetics

  • Onset of relief: 24-72h

  • Peak effects: 1 week

  • Duration: 4-8 weeks

• Limit injections to 4 times per year to minimize AEs

  • Joint infection

  • Osteonecrosis

  • Tendon rupture

Describe Glucosamine and Chondroitin Therapy in OA

Dietary Supplements

• May take 3 months for effects

• Precautions:

  • Glucosamine sulfate salt: cross-sensitivity is unknown

  • Chondroitin is derived from shark and bovine cartilage

  • Shellfish allergies

• Well tolerated; few AEs

Describe APAP therapy in OA

Not really clinically beneficial

• Considered for short-term, episodic therapy for those with limited pharmacologic options due to intolerance or C/I

• Should be scheduled, not PRN

• Hepatotoxicity is the more significant SE

• Interacts with Warfarin when taken for >14d

Describe Trolamine Salicylate therapy in OA

• Topical rubefacient available for purchase without a prescription

• May help with hand OA, but it’s questionable

Decribe Hyaluronic Acid therapy in OA

• Hyaluronate is a naturally occuring component of the cartilage and is responsible for the properties of synovial fluid which enable it to act as a lubricant and shock absorber

• This form of therapy is therefore referred to as viscosupplementation

• May be beneficial for knee OA in patients who have not responded to other therapies, but the American College of Rheumatology do not recommend the use of intra-articular acid injections for knee OA pain

• Expensive

Describe the use of Opioid Agonists in OA

• Several studies of paitents with knee OA have found the efficacy of opioids to be similar to systemic NSAIDs

• Indicated when other therapies are exhausted

• May consider joint replacement over chronic opioid usage

• Tramadol is a commonly used opioid for OA

Describe the progression of pharmacotherapy for Knee OA

Mild:

• Topical NSAID or Capsaicin

Moderate-to-Severe:

• Topical NSAID

• Systemic NSAID

• Duloxetine

• Intraarticular glucocorticoid injection

Describe Hip OA pharmacotherapy

• Systemic NSAID

• Intraarticular injection — reserved for paitents with moderate-to-severe pain when short-term relief is desired and there are contraindicateions to or failure of other treatments

• Topical therapies are not used to manage hip OA

• Duloxetine has not been studied in hip OA

Describe Hand OA Pharmacotherapy

• Topical: NSAID/Capsaicin

• Systemic NSAID: reserved for patients who do not respond to topical therapy or have OA at more than 2 sites

Describe the Pathophysiology of Rheumatoid Arthritis

• Inflammation of synovium tissue results in tissue proliferation (Pannus)

• Autoantibodies may be detected before clinical disease is present

  • Rheumatoid Factor (RF)

  • Anti-citrullinated protein antibody (ACPA)

• Inflammatory changes cause loss of cartilage, formation of chronic granulation or scar tissue, and/or tendon deformity

Describe the Clinical Presentation of RA

Symptoms:

• Symmetrical joint pain and stiffness (>30 min)

• Constitutional

  • Fatigue

  • Anorexia

  • Loss of Appetite

  • Low-grade fever

Signs

• Joint tenderness, erythema, swelling (soft/spongy)

• Rheumatoid nodules

• Joint subluxation/deformity

Describe the use of EULAR diagnostic Criteria

A score of 6 or higher indicates definite RA — higher the score, the worse it is

• Anti-citrullinated protein antibody (ACPA): highly specific and detectable early in disease

Describe the Diagnosis of RA (Aside fro EULAR)

• Radiography helps to establish the extent of cartilage destruction and bone errosion, monitor impact of medications, and to determine if therapt needs to be escalated

• Radiographic findings

  • Soft tissue swelling

  • Osteoporosis near the joint

  • Erosions (Occur late in the disease)

Describe the Joint Involvement in RA

• Usually symetrical and polyarticular

• Small joints of the hand, wrist, and feet are most frequently involved

• Elbows, shoulders, hips, knees, and ankles are also common but to a lesser extent

• Spine involvement usually occurs in the cervical vertebrae

  • Lumbar spine involvement is rare

Describe Ulnar Deviation

Describe Boutonniere Deformity

Describe Swan Neck Deformity

Describe Rheumatoid Nodules

Describe Extravascular Involvement in RA

• Systemic disease and other organ systems are involved in about 40% of patients with RA

• Extraarticular involvement is associated with release of inflammatory cytokines from the synovium

• Extraarticular disease is a marker of disease severity and is associated with increased overall morbidity and premature mortality when compared with those with RA without extraarticular disease

What are some Nonpharm therapies for RA?

• Rest

• Physical and occupational therapy

• Orthotic devices

• Weight loss

• Surgery

What three classes of Drugs are considered for RA therapy?

• csDMARD (Conventional Synthetic)

• bDMARD (Biologic)

• tsDMARD (Targeted Synthetic)

List the csDMARD drugs discussed in class

• Methotrexate

• Leflunomide

• Hydroxychloroquine

• Sulfasalazine

List the bDMARDs discussed in class

TNF-𝛼 antagonists

• Etanercept

• Infliximab

• Adalimumab

• Golimumab

• Certolizumab

• Rituximab

IL-6 Receptor Antagonists

• Sarilumab

• Tocilizumab

List the tsDMARDs discussed in class

• Tofacitinib

• Baracitinib

• Upadacitinib

Describe the use of Methotrexate in RA

• csDMARD — First-line therapy

• Usual dose: 7.5-15mg PO/SC/IM once weekly (25mg max)

• Onset of symtpom relief occurs 2-3 weeks after initiation

  • Max benefit seen in 6 months

• Oral absorption decreases with increasing doses

Describe the AEs of Methotrexate

• GI distress

• Bone marrow suppression

• Pulmonary (fibrosis, pneumonitis) — rare

• Hepatitis — cirrhosis is rare

• Photosensitivity

• Folic acid deficiency

List contraindications to Methotrexate

• Pregnant or contemplating pregnancy

• Kidney disease (eGFR <30mL/min/1.73m²)

• Liver disease or alcohol use disorder

• Bone marrow suppression

  • Leukopenia (WBC <1000/mm³)

  • Thrombocytopenia (Platelet count < 75,000/mm³)

Describe the use of Leflunomode in RA

• csDMARD

• Onset of symptom relief occurs within 1 month after a loading dose

• Pharmacokinetics

  • Long elim t½ → metabolized into an active metabolite

  • Enterohepatic circulation—cholesteyramine, an anion exchange resin, may be used to clear leflunomide more rapidly — for those who need to be off quickly

List AEs of Leflunomide

• GI distress

• Hepatitis

• Bone Marrow Suppression

• Alopecia

Describe the use of Hydroxychloroquine in RA

• csDMARD

• Studies have demonstrated efficacy in Milder RA, but it does not slow radiographic progression

• Onset of symptom relief is delayed up to 6 weeks

  • Should not be considered failed until 6 months w/o response

• Advantages:

  • May be used in pregnancy

  • No hepatic, kidney, or bone marrow toxicity

Describe the AEs of Hydroxychloroquine

• GI distress

• Ocular toxicities

  • Accommodation defects

  • Scotomas

  • Corneal deposits

• Increased skin pigmentation

• Alopecia

Describe the use of Sulfasalazine in RA

• csDMARD

• Onset of symptom relief within 2 months (longest)

• Metabolized to its active components by colonic bacteria (beneficial for IBS)

  • Sulfapyridine—antirheumatic activity

  • 5-aminosalicylic acid

Describe AEs of Sulfasalazine

• GI distress

• Severe dermatologic reactions

• Yellow-orange skin/urine discoloration (benign)

• Leukopenia

• Hepatitis

Drug interactions with Sulfasalazine

• Antibiotics can destroy the colonic flora responsible for cleaving the prodrug, thus decreasing the absorption and effectiveness of sulfasalazine

• Iron supplements bind with sulfasalazine which decreases absoprtion

• Sulfasalazine may displace warfarin from protein-binding sites, thus potentiating the anticoagulant effects of warfarin

In bDMARD therapy, what are the three types of therapeutic molecules?

• Soluble receptor antagonists: truncated froms of the cell surface that are devoid of the transmembrane and intracytoplasmic domains; bind their target cytokine while it is in the serum, theraby inhibiting the cytokine’s ability to interact with its cell surface receptor

• Monoclonal Antibodies: typically consist of the Fc portion of human IgG1 and chimeric, humanized, or fully human Fab fragments

• Cell surface receptor antagonists: biologically inactive proteins that compare for binding to the cytokine’s membrane receptors

What are some safety issues with bDARDS?

• Infection risk

  • Tuberculin skin test at baseline

  • HBV evaluation

  • Vaccinations

    • Avoid live vaccines

• Malignancy

• Injection site rxn

• Infusion-related reactions (for IV dosage forms)

• Anti-drug antibody formation (immunogenicity)

• Do not combine bDMARD medications

Describe the use of TNF-𝛼 Inhibitors in RA

• May be combined with csDMARDs

  • Less radiographic progression than oral DMARD alone

• Variable symptom relief onset

  • Infliximab: 3-7 days

  • Adalimumab: 3 months

• Heart Failure: avoid TNF-𝛼 inhibitors becayse they are associated with worsening or development of heart failure

Which TNF-𝛼 Inhibitors can be concomitantly used with Methotrexate?

Infliximab and Golimumab

“I Go with Methotrexate”

Describe the use of Rituximab in RA

• Monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes

• Onset of symptom relief within 2 weeks

• AEs:

  • Hepatitis

  • Neutropenia or thrombocytopenia

  • GI perforation

  • Hypertension

  • Hyperlipidemia

Describe the use of IL-6 Inhibitors in RA

• bDMARDS

• Sarilumab and Tocilizumab are monoclonal antibodies which antagonize IL-6 recptors

• AEs:

  • Hepatitis

  • Neutropenia

  • Thrombocytopenia

  • Hyperlipidemia

  • GI perforation

Describe the use of Janus Kinase Inhibitors in RA

• tsDMARDS

• SHOULD NOT BE USED WITH bDMARDs due to an increased risk for infection and/or malignancy

• Available as an oral dosage form

• They may be given with or without methotrexate

List the Janus Kinase Inhibitors and their clinical notes

• Tofacitinib

  • Dose adjustment in renal impairment, hepatic impairment, potent 3A4 inhibitors, moderate 3A4 inhibitors of 3A4 and 2C9

• Baricitinib

  • Dose adjustment in renal impairment

• Upadacitinib

  • No notes

Describe the AEs of Janus Kinase Inhibitors

• Infection

• Malignancy

• Venous thromboembolism

• Neutropenia

• Anemia

• Hyperlipidemia

Decribe dosing methods of Corticosteroids in RA

• Bridging Therapy: symptom relief before the onset of DMARD

• High-dose Burst: use to control acute disease flares

• Continuous low-dose: used for maintenance therapy

Describe parenteral admin of Corticosteroids in RA

• IM provides 2-6 weeks of relief but associated with systemic AEs

• Intraarticular has fewer systemic effects; useful when small number of joints affected

• Intravenous is reserved for severe, refractory symptoms.

Describe NSAID therapy in RA

• Does not modify the disease

• Only used during DMARD initiation and as needed for breakthrough pain

____________ should be started as soon as the diagnosis of RA is established

DMARD therapy

Treatment should be aimed at reaching a target of _____________________ in every patient

sustained remission or low disease activity

Monitoring should be frequent in active disease (every ____ months); if there is no improvement in disease activity by at most ___ months after the start of treatment or the target has not been reached by ____ months, therapy should be adjusted

1-3; 3; 6

______________ should be part of the first treatment strategy

Methotrexate

In patients with a contraindication to Methotrexate, ___________ or ___________ should be considered as part of the first treatment strategy

Leflunomide; Sulfasalazine

Short-term ____________ should be considered when initiating or changing csDMARDs. They should be _______ when low disease activity is achieved.

Glucocorticoids; tapered

If the treatment target is not achieved with the first csDMARD strategy, in the absence of poor prognostic factors, ____________ should be considered

other csDMARDs

If the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, ____________ should be added

a bDMARD or a tsDMARD

bDMARD or tsDMARD should be combined with a _________; in patients who cannot, __________ and tsDMARDS may have some advantages compared with other bDMARDS

csDMARD; IL-6 pathway inhibitors

If a bDMARD or tsDMARD has failed, treatment with another _________________ should be considered; if one ___ inhibitor therapy has failed, patients may receive an agent with another mode of action or a second ___ inhibitor

bDMARD or a tsDMARD; TNF; TNF

If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering ________________, especially if this treatment is combined with a csDMARD

bDMARD or tsDMARD

If a patient is in _______________, tapering the csDMARD could be considered

persistent Remission