Rheumatoid Arthritis

Past, Present, Future

Simona Parau, PGY3 Internal Medicine, Hospital of Saint Raphael

Case Presentation

50 years old man with no significant past medical history develops progressive pain and swelling of the small joints of both his hands. He complains about morning stiffness of several hours duration. He finds it increasingly difficult to engage in activities that require him to use his hands (cigarettes rolling, painting). During the next 4 years his shoulders, knees, ankles and feet begin to be affected by arthritis, with his hands begin to deform.

The Artist and the Artwork

1896 , 4 years after onset

On the Terrace , 1878

Case Presentation

The treatment prescribed by his physicians at the time consists in warm bath, visits to thermal water resorts, purges and antipyrine (medication used now days for cerumen removal). The patient relies heavily of physical exercises to keep him in shape, later gets used to nurse cats so they would keep his hands warm. By the time he turns 65, he has ankylosis of his right shoulder and several extensor tendons ruptures in his hand, causing significant deformities and difficulty with hand fine movements.

Pierre-Auguste Renoir

The evolution is toward progressive deterioration, not only articular but also systemic, with developments of paralysis, pressure ulcers, cachexia and finally death at age 70 after a severe bout of pneumonia. He continues to paint until the last minute, using his resourcefulness to device tools to aid him with daily activities. He leaves behind over 400 artworks, paintings, sculptures.

1903

Case Presentation

Blonde a la rose, 1915

Around 1912

Epidemiology and History

Prevalence: 1% in Caucasians, 0.1% African American Annual incidence: 30 new cases per 100,000 Affecting women 2-3 times more frequent then men Peak onset between age 30-55 Historical and artistic evidence that the disease is old, neolytic age skeletons discovered with erosive changes, old paintings with typical rheumatoid hands

Jacob Jordaens, The Painters Family, 1621

Pathophysiology

Adapted from- Treatment of Rheumatoid Arthritis: New Therapeutic Approaches with Biological Agents

Pathophysiology

www.nature.com

Symptoms and Physical Findings

Articular: arthritis (tumefaction, inflammatory pain) of MCP, PIP, wrists Relative symetricity, mostly poliarthritis rather than oligoarthritis Morning stiffness, usually more than 3o minutes

Symptoms and Physical Findings

Extra articular symptoms:

-skin: rheumatoid nodules, skin ulcers, gangrene, (rheumatoid vasculitis), pyoderma gangrenosum -cardiovascular: pericarditis, myocarditis, significant increase in the risk of coronary artery disease (accelerated atherosclerosis), amyloidosis, peripheral vascular disease

Symptoms and Physical Findings

Extra articular symptoms:

-eye: scleritis, episcleritis, keratoconjunctivitis sicca (associated with Sjogrens syndrome) -lung: pleuritis and pleural effusion, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans and organising pneumonia

Biological Markers
Rheumatoid

Factor:

-autoantibodies (mostly Ig M) directed against Fc

fragment of Ig G) -generally have a sensitivity around 73% and specificity of 82% -associated with more destructive disease, extra articular disease (especially vasculitis), carries worse prognostic significance and is correlated with disease activity

Biological Markers

Anti citrulinated peptide antibodies (Anti-CCP)

-autoantibodies against fillagrin, targetting a modified arginine residue -sensitivity varies from 46% to 76%, specificity as high as 96% -also predictor of more rapid radiographic progression in early RA, independent of presence of RF -sensitivity varies with kit assay, can be present (lower titers) in other diseases: SLE, active TB

Useful laboratory tests

ESR and CRP

-non specific, can be influenced by various factors

(notably ESR by hemoglobin concentration) -used for monitoring disease activity and therapeutic response to DMARD -persistently elevated ESR/CRP can predict radiographic damage progression even in early RA -they are part of DAS 28 score (Disease Activity Score), and respectively DAS CRP, a tool that is used for monitoring disease activity

Imaging

Early radiographic changes are: swelling of the soft periarticular tissue, periarticular band like osteoporosis, marginal erosions especially in MCP and PIP area Late changes: loss of joint space, subluxations and massive destruction of affected joint with distortion of architecture ! Only 15-30% of patients have radiography changes upon diagnosis

Diagnosis

American Rheumatology Association criteria: (ARA) at least 4, the first 4 or them must be present for more than 6 weeks Arthritis of 3 ore more joint areas- soft tissue fluid/swelling observed by physician Arthritis of hand joints (>1, wrist, MCP, PIP) Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes

1. 2. 3. 4. 5. 6.

Differential Diagnosis

include but are not limited to: -other connective tissue disorders: seronegative spondilarthropaties, psoriatic arthritis, infections arthritis, SLE, MCTD -osteoarthritis, soft tissue rheumatisms -if presents with systemic manifestations, broad differential diagnosis

Principles of Treatment

Multidisciplinary approach Patient education and counseling: rest, physical activity /exercise, joint protection, occupational therapy, psychological counseling and support groups Vaccinations, protection against early atherosclerosis, treatment of osteoporosis Corrective surgery /joint replacements Medical treatment targeted at both symptoms and most of all joint preservation

Evaluation of Disease Activity

ACR 70%, ACR50%, ACR20% response criteria improvement in number of tender and swollen joints, pain, disability , acute phase reactant, patient and physician global assessment of disease

DAS 28 score (Disease Activity Score) total number of tender and swollen joints, ESR,VAS (Visual Analogic Scale) for general health assessment DAS CRP now used more frequently

<2,6 remission, 2.6-3.2 low disease activity, 3.2-51 moderate disease activity, >5.1 high disease activity

Disease Modifying Anti Rheumatic Drugs (DMRDS)

Hydroxicloroquine Sulfasalazine Methotrexate Leflunomid Azthyoprine, Cyclosporine, Cycophosphamide, Gold Salts TNF alfa receptor blockers: Infliximab, Etanercept, Adalimumab Monoclonal antibodies against B lymphocytes: Rituximab IL 1 receptor inhibitors: Anakinra Costimulation blockers: Abatacept IL 6 receptor blockers: Tocilizumab

Early RA-The Facts

Joint destruction starts early in the course of disease Proven by radiographic evidence of joint erosion and narrowing Fuchs et al. (J.Rheumatol. May 1989) -radiologic abnormalities are present in most patients seen by a group of rheumatologist within the first 2 years of disease van Der Heijde et al (Arthritis Rheum. Jan 1992) -the rate of radiographic progression of disease was significanly higher in the first year of follow up than in the subsequent two years

Methotrexate

Inhibits dihidrofolate reductase (DHFR), inhibits purine and pyrimidine synthesis Decreases RF, IL1, IL6 production Administered orally, im, sq, one weekly in doses ranging from 7.5 mg to 25 mg Proven to decrease the number of painful joints, swollen joints, physician and patient global assessment of disease activity, delay radiography progression and overall decrease mortality alone or in combination with other DMARDs

Methotrexate

Adverse effects include hepatitis, pulmonary toxicity (fibrosis, hypersensitivity pneumonia, BOOP, infections) , myelosuppresion, stomatitis, rash and GI upset Needs monitoring of CBC, LFTs, every 4-8 weeks, needs careful questioning about respiratory symptoms, symptom monitoring for gastrointestinal distress Teratogenic, both for females and males

Sulfasalazine

Unclear mechanism of action, possible inhibition of NFKappaB, promotes macrophages apoptosis Dosing starts at 500mg/day, therapeutic dose usually 2g/day, can be increased to 3g/day Efficacy proven in RCT against placebo, proven to delay radiographic progression, both alone and in combination with Methotrexate Adverse effects include rash, hepatitis, pneumonitis, agranulocitosis, (idiosyncratic) nausea/vomiting headaches, anemia (dose dependent), oligospermia Monitor CBC, LFTs every two weeks to three month

Inhibits mytocondrial enzyme DHODH, inhibits synthesis of pyrimidines Dose: 20mg/day Eficacity: equal to MTX in a two year follow-up RCT, equal to SSZ, better in combination with MTX or Cyclosporine Adverse effects: hepatitis (reversible with discontinuation or dose reduction), HTN especially when combined with NSAIDS, cytopenia, diarrhea, nausea, rash, alopecia Requires contraceptive measures as teratogenic and with long life elimination, do not use if pregnancy is desired in next 1-2 years Monitor LFTs, CBC, monthy to every three month

Leflunomide

Hydroxicloroquine

The least toxic of the DMARDs Mechanism of action in RA: unknown Efficacy : recommended only in mild to moderate disease, part of various combinations Adverse effects are mainly GI upset, serious ocular, retinopathy (completely reversible with early discontinuation), skin pigmentation, neuropathy, rare cases of agranulocytosis and hepatitis Not teratogenic, safe during pregnancy and lactation Monitoring: need for baseline and periodical ocular exam

Various Agents
Azathioprine inhibitis ribonucleotide synthesis, reasonable disease control, adverse effects GI problems, cytopenia infections, not teratogenic, safe in pregnancy Cyclosporine calcineurin inhibitor, decreasing pro-inflammatory cytokine synthesis, used alone or in combination with MTX, adverse effects include nephrotoxicity, hypertension, headache, hyperglicemia Cyclophosphaminde used in the treatment of rheumatoid vasculitis Myelotoxicity, hemorrhagic cystitis are among the adverse effects

Combinations of DMARDS

Proven in RCTs to be more efficacious than one DMARD alone Various combinations can be used, most of them based around MTX: MTX+SSZ, MTX +HQ, MTX+Cy, Higher rates of clinical response and lower progression of erosion , at a level similar to the one achieved with biologic were noted with triple combination: MTX+SSZ+HQ Trials evaluating TNF blockers versus triple combination therapy are currently on the way!

TNF alpha blockers

TNF a blockers in the treatment of RA, NEJM, 2006

Infliximab

Chimeric (human murine) antibody against TNF alpha, binds to both soluble and membrane bound TNF inhibiting TNF-receptor interactions Administered intravenously every 4-8 weeks, at a dose of 3-6 mg/kg Is given concomitant with MTX or another DMARD in order to prevent formation of antichimeric antibodies Proven in RCT to reduce inflammation, disease progression, improve functional status, more rapid action than DMARDs More effective in combination with MTX or another DMARD than MTX/other DMARDs alone Unclear yet if more effective than combination therapy with DMARDS

Etanercept

Adalimumab

Recombinant soluble p75 TNF receptor, binds to soluble TNF only preventing interactions with its receptor Administered usually sq at doses 25 twice weekly

Recombinant humanized monoclonal antibody against TNF Administered sq at a dose of 40mg weekly

Do not require addition of MTX but the addition of the latter leads to better outcomes Have the advantage of being self administered

When to start a biologic agent?

In patients with active RA in whom there has not been a satisfactory response to one or more conventional DMARDs such as Methotrexate Active RA: >6 painful joints>3 swollen joints, ESR>30mm at 1 hour, > 45 minutes of morning stiffness OR a DAS28 score>5.1 Failure to an adequate therapeutic trial with at least 2 standard DMARDs, for at least 6 month of therapy at standard/maximal doses unless significant toxicity National health policies and insurance coverage have a significant impact on the decision to start a biologic agent due to high cost ($10000-$25000 annual)

Selection of patients

Screening for tuberculosis needs to be performed before initiation, patients with latent and active TB should be adequately treated, Patients with concomitant severe infections should be excluded, caution is necessary in hepatitis B and C and HIV positive patients (small series treated safely) Patient with prior malignancies are almost always excluded Contraception is warranted and pregnancy will lead to stopping the TNF blocker (no data to asses safety) Caution is requires in patients with heart failure and suspicion of demyelinating disease

Adverse effects TNF blockers

Common minor : injection site reaction, infusion reaction, rare: lupus like syndrome, aplastic anemia Major side effects: increases risk of infections, especially pulmonary and skin infection Primary tuberculosis and reactivation of tuberculosis are significantly higher than in general population and in population with RA Increase in the risk for lymphoma (not clear , there is a preexisting relationship between RA and lymphoma Worsen preexistent heart failure Exacerbation of preexisting multiple sclerosis

Anakinra

Recombinant human IL 1 receptor antagonist Given in combination with MTX in patients with moderate to severe RA refractory to other DMARDs Overall efficacy is lower than TNF blockers Dose: 100mg sq once daily Adverse effects include: site injection reaction, risk of infections comparable with MTX treated patients, cytopenias May worsen asthma, needs reduced dosing interval in CKD

Rituximab

Chimeric anti CD 20 monoclonal antibody that leads to a selective B cells depletion, removing the clones responsible of pathogenic antibodies Dose :500-1000 mg infusion, repeated after 2 weeks Proven efficacy alone, but better in combination with MTX or Cyclophosphamide, tested in patients refractory to MTX / TNF blockers Adverse effects: infusion reactions (rash, pruritus, nausea, hypertension) Risk of serious infections comparable with Methotrexate, reactivation of viral illnesses (PML, CMV, hepatitis B)

Abatacept

Fusion protein , works by specifically inhibiting full activation of T cells, binds to CD80 and CD86 blocking interaction with CD28 (co-stimulatory signal) Shown to be effective in combination with MTX, slowing radiographic progression of MTX refractory disease Shown to be also effective in patients who were refractory with TNF blockers Adverse effects consist in infusion reactions and infections No benefit from associations with TNF blockers Cost of therapy: $1350/month

New alternatives
Tocilizumab -humanized monoclonal antibody directed against IL6 receptor -good results as monotherapy in refractory to MTX patients, approved in Japan, trials on the way

Autologous Stem Cell Transplant -extinction of autoreactive lymphocyte clones -most of the patients still required DMARDs and reactivations of disease occurred eventually

Symptomatic Treatment
NSAIDs -provide pain relief and improve quality of life -significant toxicity: gastric, renal, hepatic -Cox2 selective inhibitors are a possible choice but limited use by specific cardiovascular toxicity

Glucocorticoids -good control of the inflammation, but do not modify disease progression -used as bridging therapy until DMARDs become active, but many patients are unable to be weaned off steroids - intra articular use to decrease inflammation -can be used in high iv doses (pulse therapy) for very active disease

Joint destruction occurs early in disease and warrants aggressive treatment to prevent future disability Referral to a Rheumatologist should be done early so treatment should not be delayed There are various choices for DMARDs, lack of response or adverse effects to a particular one should prompt initiation of another Combinations of DMARDs are usually required for adequate disease control, biologics hold an increasingly more important role in therapy at the present time Frequent monitoring is necessary because of the significant adverse effects of the medication used

Conclusions

Gartlehner et al. The Comparative Efficacy and Safety of Biologics for the Treatment of Reumatoid Arthritis: A Systematic Review and Metaanalysis, Journal of Rheumatol., 2006; 33:12 Proudman et al. Response Driven Therapy with Conventional Disease Modifying Antirheumatic Drugs Can Achieve Hihg Responses with Minimal Glucocorticoid and NSAID use, Semin. Arthritis Rheum, 2007; 37:99-111 Taylor P. Clinnically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis, UpToDate, 2007 Siddiqui MA. The efficacy and tolerability of newer biologics in rheumatoid arthritis: best current evidence, Curr. Opin. Rheum, 2007, May ; 19(3):308-13 Scott D.L., Kingsley G.H. Tumor Necrosis Factor Inhibitors for Rheumatoid Arthritis, NEngl.JMed, 2006, 355:704-12 Keane, J. TNF Blocking agents and tuberculosis: new drugs illuminate old topic, Rheumatology; 2005; 33,714-720 Gaffo et al. Treatment of Rheumatoid Arthritis, Am J. Heatlt-Syst. Pharm, 2006;632451-65 Boonen et al. How Renoir coped with rheumatoid arthritis, BMJ, 1997;315: 1704-1708

References

Thank You!

Dr. Odalis Abreu Lanfranco Dr. Lalaruk Hayder Dr. Yuka Kiyota Assoc. Prof. Simona Rednic

Pierre-Auguste Renoir 1841-1919