Rheumatology Overview, 2008Focusing on RA and SLE

Jonathan Graf, M.D.Assistant Adjunct Professor of Medicine, UCSF

Division of Rheumatology, San Francisco General Hospital

Arthritis - Misconceptions

• “You’re an Arthritis Doctor. What’s it like taking care of so many old patients”

• “Are all of your patients in wheelchairs?”

• “Arthritis is not a big deal because it’s not life-threatening”

All Arthritis Patients are Old

• Many forms of Arthritis

• Rheumatoid Arthritis commonly affects young women of childbearing age

• Osteoarthritis affects younger people who run, have traumatized their joints, are overweight, etc….

• Gout can affect people of all ages

Wheelchairs and Canes

• Thanks to recent advances and medical research, not as many face life in a wheelchair

• Treatments for many inflammatory arthritic conditions such as Spondylitis and Rheumatoid Arthritis have improved dramatically

• Joint replacement surgery has improved outcomes in Osteoarthritis

Arthritis is not Life-Threatening

• Systemic inflammatory diseases that cause arthritis can affect other organs and lead to life-threatening complications

• Chronic inflammation has now been linked to heart disease

• Advanced Osteoarthritis limits mobility and can lead to secondary health problems (obesity, heart problems, etc…)

• An in cases that aren’t life-threatening, since when is living in pain not life-altering/life-imparing. Judgement call!!

ArthritisAll forms of arthritis are not created equal

• Inflammatory– RA– SLE– Crystalline (Gout)– Vasculitis

• Non-Inflammatory– Osteoarthritis

• “Arthritis”-like diseases– Fibromyalgia

Inflammatory Arthritis

Joint swelling

Joint warmth

Joint redness

Joint pain and stiffness

Morning>Afternoon symptoms

Worse with rest, better with use (gelling)

Can Have Systemic Components

Inflammatory Arthritis- A Component of Rheumatic Diseases

• Arthritis is a common, unifying feature to a whole host of systemic auto-immune and inflammatory diseases!!!

• Characteristic pattern may vary by disease• Crystals and inflammatory reaction

– Gout, pseudogout• Rheumatoid Arthritis• Seronegative Spondyloarthropathy

– Ankylosing spondylitis– Psoriatic Arthritis– Reactive Arthritis– Inflammatory Bowel Disease Associated Arthritis

Inflammatory Arthritis, Diseases

• Lupus• Scleroderma• Myositis• Hashimoto’s Thyroiditis• Sjogren’s Syndrome• Many More!!!!!• Arthritis is a common, unifying feature to a whole

host of systemic auto-immune diseases!!!

Rheumatoid Arthritis

• One cause of inflammatory arthritis• Systemic inflammatory disease, primarily

involving the synovial membrane of diarthrodial joints

• Prevalence in North America between 1-2%• Most prevalent in women of child-bearing

age (4th-6th decade)• Can occur in any person at any age

ACR Criteria for Diagnosis of RA (4 of 7)

• Morning Stiffness>1 hr. duration

• Arthritis of 3 or more joints

• Arthritis of the hand joints

• Symmetric arthritis

• Rheumatoid nodules

• Serum rheumatoid factor

• Radiographic changes

RA, Etiology

• Probable background genetic susceptibility (multiple genes/risk factors involved)– Concordance rates 15-30% identical twins

– 2.5-3.0 times more prevalent in Women>Men

• Likely environmental triggers in people with genetic susceptibility– Disease of the New World, ? 16th C. Ohio river valley

– Not seen until late 18th century in Europe

Genetic Risk Factors

• Family history

• Female Sex

• Specific genes: HLA-DR4

• Specific region in HLA DRB1 gene confers increased risk of RA and severity

Non Genetic Risk Factors

• ? Bacterial or Viral Agent– Parvovirus, Hepatitis, Lyme, and Rubella

• ?Environmental Triggers– Tobacco, Caffeine

RA, Clinical FeaturesHow to Differentiate from other Osteoarthritis

• Symmetric polyarthritis

• Usually small-medium joints are involved

• Generally chronic disease (20% acute onset)

• Often leads to erosive, deforming, and disabling disease

• 20% have extra- articular manifestations

Ethical Question: Does a disease have to be “life-threatening” for it to be considered important?..... The ravages of a chronic destructive arthritis.

How does this person walk????

RA is a Systemic Disease – Rheumatoid Arthritis can cause

Blindness• Rheumatoid Nodules • Interstitial Lung

Disease• Vasculitits• Felty’s Syndome• Ocular Disease• Secondary Amyloid

Rheumatoid Nodules

RA – Vasculitis. Rheumatoid Arthritis can be life-threatening

RA – Synovitis: This is what an inflammatory arthritis looks like. 81 YO female with Rheumatoid Arthritis

RA – R>L Knee Synovitis: 81 YO Female Patient

RA – Rheumatoid Nodules

Normal Joint Histology

• Synovial lining 1-2 layers of synoviocytes

• Sub-lining layer of loose connective tissue and blood vessels

RA Joint Pathology

• Inflammation, capillary leak, fibrin deposition

• Synovial Hyperplasia• Cellular infiltrate

– Macrophages

– Lymphocytes

– Can resemble lymphoid tissue in 1/3

RA Pathology

• Synovium becomes laden with macrophages, fibroblasts, and multi-nucleated giant cells (resemble osteoclasts)

• Synovial membrane (pannus) expands, actively invades and erodes surrounding bone and cartilage

Rheumatoid Arthritis

• Disability costs are high, both in terms of direct and indirect medical costs

– 35% of patients with 10 years disease duration are work-disabled

– Decline from 50% rate reported in 1987Arthritis Rheum. 2008 Mar 27;59(4):474-480

RA: Chronic Joint Destruction and Disability – What We Try to Prevent

Ra: Traditional Treatment Paradigm

• Pyramid of therapy– Start conservatively

– Gradually ascend the pyramid in order of potency and toxicity of therapy

– Only the most severely affected patients receive immuno-supressive, DMARDs

– DMARD therapy begun only after period of significant delay

Re-Thinking the RA Treatment Pyramid

• Emphasizes earlier diagnosis and initiation of therapy with disease modifying anti-rheumatic drugs

Early RA: The Window of Opportunity to Intervene

The Window of Opportunity Eventually Closes for Many….

• Chronic disease progression leads to permanent joint deformity, destruction, and disability

• Empirically, RA is a different disease the longer disease activity progresses without effective control– More difficult to suppress

activity and treat– More extra-articular disease?

ACR RA Practice Guidelines 2002

• Most patients with Rheumatoid Arthritis should be evaluated expeditiously

• Treatment with DMARD instituted within 3 months of diagnosis

• Goals are to prevent or control joint damage, prevent loss of function, and decrease pain

RA Pharmacologic Therapy: DMARDs

• Methotrexate• Leflunomide (Arava)• Sulfasalazine• Azathioprine• Mycophenolate Mofetil• “Corticosteroids”• “Hydroxychloroquine”• “Minocycline”

Methotrexate

• Cornerstone DMARD, now 1st line therapy, alone or in combination for mod.-severe RA

• Blocks Dihydrofolate reductase• Inhibits production of tetrahydrofolate, a single

carbon donor• Leads to diminished production of purines and

inhibits DNA synthesis (although there are other mechanisms likely involved)

• Reduces proliferative potential of replicating immune and inflammatory cells

Methotrexate• Long-term benefits in symptom improvement &

retardation of joint damage

• Long term – well tolerated with acceptable safety profile (no ETOH)

• Available as IM/liquid/tablet preparations

• Starting dose 7.5 mg/WEEK – up to 25 mg/wk

• Renally cleared – be careful and adjust dose

Methotrexate Adverse Events• GI - Mucositis, diarrhea, abdominal pain• Hematologic - Cytopenias, macrocytosis• Hepatic- Transaminitis, fibrosis, and cirrhosis• Pulmonary - Hypersensitivity pneumonitis, pulmonary fibrosis• Infections• Neoplasia - reversible lymphoproliferative disorder,

lymphoma, and leukemia• Accelerated nodulosis and vascultitis• Reproductive – abortifacient and teratogen

– Must use birth control and d/c drug 2-6 months before planned pregnancy

Combination DMARD Therapies: Some Step Up, Others Step Down

• Methotrexate +SSZ +Plaquenil +/- Prednisone

• Arava + SSZ + Plaquenil +/- Prednisone

• Methotrexate X Arava ----- Generally not done

• More and more, combination therapies of DMARDs and Biologic medications being used earlier in the course of treatment

Why Move Towards Combination Regimens with Biologics??

The Current Pyramid Paradigm

• Early initiation and titration of DMARD• If incomplete response to DMARD alone, after reasonable

titration, addition of biologic recommended

Biologic Therapies

• What is meant by the term Biologic Therapy?

• Double meaning:– Organic compounds made by living cells

• As opposed to products from a chemistry lab

– Modify biologic responses• Antibody-antigen interactions

• Cytokine-receptor interactions (both ends)

• Cell signaling proteins, inhibitors, or ligands

Families of Biologic Therapies

• Anti-Tnf medications – Etanercept (cytokine receptor fusion protein)– Infliximab (anti-cytokine antibody)– Adalimumab (anti-cytokine antibody)

• B-cell depleting agents (monoclonal antibody)– Rituximab

• T-cell costimulation inhibitors (receptor-ligand )– Abatacept

• Il-1 Inhibitors (Il-1 cytokine receptor decoy)– Anakinra

Anti-TNF Family of Biologics

Anti-Tnf medications Etanercept (cytokine receptor fusion protein)Infliximab (anti-cytokine antibody)Adalimumab (anti-cytokine antibody)

TNF Effects: The Good and the Bad• Good: TNFa and TNFb regulate biological functions necessary

for normal inflammatory and immune responses.– TMF-a absolutely essential for granulomatous host defenses against

intracellular bacteria – MTb, fungal infections, listeria

• Bad: TNF-a binds membrane-bound TNF receptors and mediates pro-inflammatory processes implicated in inflammatory arthritis.

Man-Made Advances in TNF Biology

• The family of anti-TNF therapies– Etanercept (Enbrel)– Infliximab (Remicade)– Adalimumab (Humira)

Etanerceot Infliximab Adalimumab

Etanercept

• Etanercept recombinant, dimeric fusion protein

• Consists of the soluble human p75 tumor necrosis factor (TNF) receptor coupled to the Fc fragment of human IgG1 lacking the CH1 domain.

• Binds soluble TNF-a and TNF-b and prevents activation of TNF-Rs

Infliximab

• Infliximab is a “humanized” monoclonal antibody

• TNF binding region derived from mouse anti-TNF monoclonal antibody

• Attached to constant region of human IgG1 kappa antibody.

• Chimeric molecule not 100% human

Adalumimab

• Adalimumab is a recombinant, fully human monoclonal IgG1 kappa antibody.

• All monoclonal anti-TNFs bind membrane bound and soluble TNF (May have added benefit leading to clearance or apoptosis of cells expressing surface TNF)

• All monoclonals bind only TNF-alpha (not TNF-b)

– May explain differential effects of anti-TNF medications in IBD

The Anti-TNF Clan

• Differences between agents: Enbrel Remicade Humira

Ab N Y Y

Form. Injection Infusion Injection

Human Y N Y

T ½ S L L

Contraindications• History of latent tuberculosis unless/until they have completed an adequate

courses of prophylactic therapy (Duration up for debate)

• Active acute or chronic infections (HCV may become exception)

• Active or suspected malignancies.

• Hypersensitivity to an anti-TNF agent or mouse product (infliximab)

• Anti-TNF agents in the setting of hepatic disease or renal failure has not been studied.

• Anti-TNFs are generally contraindicated in patients with moderate or severe congestive heart failure (some have black box warning)

• History of demyelinating disease

Anti-TNFs: Like all success stories, there are always

complications

• Increased risk of infections! (OR of 2.0 for serious infection in large meta analysis published in JAMA 2006)

• Increased malignancy risk: Always thought of as a theoretical risk, now controversial evidence that RA patients may be at increased risk of lymphoma and/or solid tumors

• May worsen symptoms of congestive heart failure.

Anti-TNF Therapy: Allergic and Idiopathic Reactions

• Dermatologic reactions– Localized: Mild-moderate injection site reactions– erythema, pruritis, pain, and/or swelling– reactions are commonly self-limiting early in the course of therapy.– FDA has recent case reports of Steven’s Johnson and TEN with all

three

• Infusion reactions, especially with infliximab– within 1-2 hours after receiving the therapy– fever, chills, urticaria, and cardio-pulmonary symptoms– antibody mediated serum-sickness type of syndrome also reported

that’s separate than from typical infusion reaction

Systemic Lupus Erythematosis

• Systemic Disorder, involving multiple organs in multiple ways

• Women:Men = 9:1• African American/Caribbean in US/UK:

Dz. is 3 times more common• Peak Age of Onset 20’s & 30’s• Incidence has tripled since 1970’s to

5.56/100,000 population

SLE: ACR Criteria:4 of 11 Criteria without better explanation (Not diagnostic)

• Malar Rash

• Discoid Rash

• Photosensitivity

• Oral Ulcers

• Arthritis

• Serositis

• Renal Disorder

SLE Criteria Cont.

• Hematologic Disorder

• Immunologic Disorder

• ANA

• Neurologic Disorder

Malar Rash

• Fixed malar distribution of erythema, flat or raised

Discoid Rash

• Erythematous raised patches with keratotic scaling and follicular plugging; some atrophic scarring in chronic lesions

Photosensitivity

• Skin rash as an unusual reaction sunlight, by patient history or physical examination

Oral Ulcers

• Oral or nasopharyngeal ulcers, usually painless, observed by a physician

Arthritis

• Non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

Other SLE Criteria

• Serositis– Pleuritis (convincing

history of pleuritic pain or rub heard by a physician or evidence of pleural effusion

– Pericarditis (documented by EKG, rub, or evidence of pericardial effusion)

• Renal Disorder (can lead to renal failure)– Persistent proteinuria

>0.5g/day (or>3+)

– Cellular casts of any type (glomerulo-nephritis)

Hematologic Abnormalities

• Hemolytic anemia (usually coomb’s positive)

• Leukopenia (WBC < 4,000 on at least 2 occasions)

• Lymphopenia (<1500 on 2 or more occasions)

• Thrombocytopenia (PLT<100,000 on 2 or more occasions)

Immunologic DisorderOne of the Following

• Anti-dsDNA

• Anti-Smith

• Positive findings of anti-phospholipid Abs– Abnormal level of either IgG or IgM CLIP Abs– Positive test for Lupus Anticoagulant (RVVT)– False positive RPR/VDRL > 6months neg. FTA

Positive ANA• An abnormal titer of ANA in the absence of

drugs known to be associated with “drug-induced lupus syndrome”

Neurologic Disorder

• Classically defined only as:– Seizures (in the absence of other causes)– Psychosis (in the absence of other causes)

• Other CNS manifestations – Headaches– Cognitive dysfunction

Organ System Involvement in Flares of SLE, Hopkins Cohort:1991• Constitutional 66%• Musculo-skeletal 58%• Dermatologic 47%• Renal 22%• Neurologic 21%• Hematologic 17%• Serositis 12%• Pulmonary 7%

Permanent Organ Damage in SLE, Hopkins Cohort: 1991

• Musculo-skeletal 25.2%• Neuro-psychiatric 15%• Ocular 12.6%• Renal 11.7%• Pulmonary 10.4%• Cardiovascular 10.1%• GI 7.4%• Skin 7.4%• Peripheral Vascular 5.5%• Malignancy 2.5%• Premature Gonadal Failure 1.2%

Cyclophosphamide

• Pulse IV therapy mainstay for Diffuse Proliferative GN secondary to SLE

• Less-studied, but significant therapy for severe systemic manifestations– CNS vasculitis– Transverse Myelitis– Pulmonary capillaritis/ diffuse alveolar

hemorrhage/severe interstitial pneumonitis

Cyclophosphamide Therapy:Glomerulonephritis

• 0.5 – 1.0 g/m2 dosed monthly for 6 months

• 1 mg/kg/day concomitant prednisone Rx.

• Dosed every 3 months for next 18 months

• 5-year renal survival rates: 60-90%

• Frequent monitoring– Cell counts nadir 10-14 days

post therapy– Urinalysis: Hemorrhagic cystitis Annals of Internal Medicine, 2001

Cyclophosphamide: Side Effects• Short-Term

– Nausea, alopecia– Immunosupression, opportunistic infections– Cytopenias

• Medium-Term– Hemorrhagic Cystitis

• Long Term– Transitional Cell Carcinoma– Hematologic malignancies– Infertility

• Non-responders (to follow)• Relapses: Re-treat or try alternative therapies

Minimizing Toxicity: Other options?

• Lower, more frequent dosing of Cytoxan

• Shorter courses of induction therapy followed by maintenance therapy– Azathioprine– Mycophenolate Mofetil

• Induction therapy with MMF

Mycophenolate Mofetil

• Hydrolyzed to active form: Mycophenolic acid• Inhibits Inosine Monophosphate Dehydrogenase: Blocks purine

synthesis• Affects activated/dividing lymphocytes• Originally developed to prevent allograft rejection• Dosed: 500 Mg PO BID – 1.5g PO BID

Potential Novel Therapies

• Anti B-cell therapies

• Anti-T-cell therapies– Co-stimulatory signal blockade

• Vaccination Strategies

• Marrow Ablation - Transplant

B-cell Depleting Therapies:Rituximab

• Attractive for diseases characterized by aberrant, pathologic auto-antibody formation (SLE, APLA, ITP)

• CD20 expressed almost exclusively on B-cells

• CD20 not expressed on Plasma cells• Anti-CD20 Antibody binds B-cells and

depletes B-cells through unclear mechanism(s)– Apoptosis, reticulo-endothelial system

clearence, etc…

Rituximab

• (Rituximab) approved to deplete B-cell lymphomas

• Phase I/II open label, dose-escalation study of 18 patients with non-threatening SLE

• B-cell depletion correlated with improvement in rash, arthralgias, fatigue

• Case reports of use in severe, refractory disease with some possible utility

The Sun is Rising for Patients with Rheumatic Diseases: The Future is Bright