Rheumatoid Arthritis. By: Hadi Esmaily (PharmD., BCCP, MBA) Department of Clinical Pharmacy, Shahid Beheshti Medical University

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2 Rheumatoid Arthritis By: Hadi Esmaily (PharmD., BCCP, MBA) Department of Clinical Pharmacy, Shahid Beheshti Medical University

3 Introduction RA is a Chronic, Systemic, Inflammatory disorder of unknown etiology that primarily involves synovial joints It is typically symmetrical, and leads, to destruction of joints due to erosion of cartilage and bone, causing joint deformities It results in significant locomotor disability within years in patients who do not fully respond to treatment

4 RA Arthritis, arthrosis, arteritis! Lab tests? RF, Anti cyclic citrullinated peptide (CCP) antibody RA criteria's Morning stiffness, poly arthritis, arthritis in MCP or wrist not DIP, symmetric, SC nodules, radiographic erosion Mortality Cardiovascular disease

5 RA Epidemiology: RA is the most common chronic inflammatory arthritis Affects about 1% of adults Onset usually occurs in the fourth & fifth decade of life It is two to three times more prevalent in women than in men

6 Signs & Symptoms Painful, warm, swollen joints of the hands and wrists most commonly Pain sometimes affecting elbows, neck, shoulders, hips, knees, and/or feet Stiffness of affected joints in the morning that improves during the course of the day Fatigue Fever Development of nodules under the skin, especially at the elbows A general feeling of being unwell (Malaise)

7 RA Etiology: Environmental Virus like particles have been isolated from synovial effusions in RA Some RA patients exhibit evidence of a recent parvovirus infection Hormonal Genetic Identical twins show 30%-50% concordance for the disease First-degree relatives of patients with RA have about a 2-3 fold increased incidence Associated with HLA DR-4 and DR-1

8 RA Etiology: T cell activation B cell activation Polycyclic 70% Monocyclic 29% Progressive 10%

9 RA course: Treatment Type 1 Type 2 Type 3

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21 Extraarticular feature: SC nodules Rheumatoid vasculitis Pleuropulmonary & cardiac Neurologic Eye Osteoporosis Lymphoma

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23 RA Treatments Goals: Reduce pain Prevent deformity & loss of normal joint function Maintain normal physical, social & capacity to work

24 Treatments Non pharmacologic - Patient education - Local rest of inflammed joint - Weight reduction - Walking aid - General exercise to prevent contracture & muscle atrophy Pharmacologic

25 Treatment The treatment of RA is directed toward the control of synovitis and the prevention of joint injury The choice of therapies depends 1. The severity of disease activity when therapy is initiated 2. The response of the patient to prior therapeutic interventions

26 Principles of Treatment Early recognition and diagnosis Care by an expert in the treatment of rheumatic diseases (e.g. rheumatologist) Early use of disease-modifying antirheumatic drugs (DMARDs) for all patients diagnosed (Max 3 month) Importance of tight control with target of remission or low disease activity Use of NSAIDs & glucocorticoids, only as adjuncts to therapy

27 Anti-Inflammatory drugs Versus DMARDs DMARDs can control synovitis and slow, or even stop, radiographic progression 1. The Nonbiologic (or conventional synthetic) DMARDs 2. Biologic DMARDs

28 Pretreatment Evaluation 1. General testing for all patients: A baseline CBC, SrCr, ESR, CRP & aminotransferases 2. Serologic testing for hepatitis prior to MTX, leflunomide, or biologic DMARDs 3. Ophthalmologic screening for hydroxychloroquine use 4. Testing for latent tuberculosis

29 Treatment Types Rapidly acting antiinflammatory medications (NSAIDs & Glucocorticoids) DMARDS Non-Biologic DMARDS: 1. Hydroxychloroquine 2. Sulfasalazine 3. Methotrexate 4. Leflunomide

30 Biologic DMARDS 1. TNF-alpha inhibitors: Etanercept, Infliximab, Adalimumab, Gol imumab, & Certolizumab Pegol 2. IL-1 receptor antagonist: Anakinra 3. IL-6 receptor antagonist: Tocilizumab 4. T-cell costimulation blocker: Abatacept (CTLA4-Ig) 5. Anti-CD20 B-cell depleting monoclonal antibody: Rituximab

31 Early Use of DMARDs Much of the joint damage that ultimately results in disability begins early in the disease course Start early Mild active RA: NSAID & DMARD e.g. hydroxychloroquine or sulfasalazine Moderate-Severe RA: NSAID or glucocorticoid (based on disease activity) & MTX When resistant to initial DMARD: 1. Treat with a combination of DMARDs (eg, MTX plus either a TNF inhibitor or SSZ and HCQ) 2. Different DMARD (eg, leflunomide or a TNF inhibitor)

32 Principle of DMARDs Frequent monitoring of activity by assessing history, the physical examination, acute phase reactants, and use of measures of disease activity The prompt use of more aggressive DMARD therapy (eg, MTX in patients being treated with hydroxychloroquine or sulfasalazine) Treatment of all patients diagnosed with RA with DMARD therapy Use of anti-inflammatory therapies, including NSAIDs and glucocorticoids, to help control symptoms until DMARDs take effect

33 Mild Severity of Disease < Five inflamed joints Mildly elevated or normal ESR & CRP No extra-articular disease No evidence of erosions or cartilage loss on plain radiographs of the hands, wrists, and feet Low levels of measures of disease activity such as the Disease Activity Score in 28 joints (DAS28)

34 Start Use HCQ and/or SSZ as the initial DMARD in most patients with mildly active RA Those with minimal or low levels of disease activity and those who are seronegative for RF and Anti-CCP antibodies These two drugs do not impair female fertility and are relatively safe if continuing use is essential in pregnancy If patients have greater disease activity, or if an adequate trial (12-24 weeks) of these medications proves inadequate MTX, or a combination of DMARDs

35 Assessment & Monitoring Assessment of 1. Disease activity 2. Drug toxicities

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37 Drug Toxicity Monitoring NSAIDs: Physical Exam: Dark/black stool, dyspepsia, nausea/vomiting, abdominal pain, edema, shortness of breath Laboratory Tests: CBC yearly, LFTs, creatinine

38 Drug Toxicity Monitoring Hydroxychloroquine Visual changes, periodic funduscopic and visual field examination

39 Drug Toxicity Monitoring Sulfasalazine: Physical Exam: Symptoms of myelosuppression, photosensitivity, rash Laboratory Tests: CBC, aminotransferases & creatinine every month for the first 3 months or after increasing the dose, every 2 month for months 3-6, then every 3 month

40 MTX MTX is contraindicated in several groups of patients: Women who are contemplating becoming pregnant Women who are pregnant Patients with liver disease or excessive alcohol intake Patients with severe renal impairment (egfr rate<30 ml/min)

41 MTX dosing MTX is given in a single weekly dose (usually orally) Initiation dose is between mg once weekly for most patients, depending upon the degree of disease activity, the size and age of the patient, the presence of comorbidities, and renal function. A 70-year-old patient weighing 55 kg with moderately active disease 7.5 mg once weekly A 30-year-old patient weighing 80 kg with highly active disease 15 mg once weekly An egfr <60 ml/min 7.5 mg once weekly

42 Pearls Dose after 4 weeks by 2.5 mg (one tablet) to 5 mg per week at intervals no more frequent than every month The usual maximum dose is 25 mg/week For patients in whom mg of MTX orally once weekly is ineffective or is poorly tolerated because of GI symptoms, a trial of SQ MTX administration is an alternative to switching to another DMARD or to adding a TNF inhibitor.

43 Pearls Patients receiving MTX should also receive daily supplementation with folic acid MTX has a faster onset of action, comparable or greater efficacy and better long-term tolerance compared with other nonbiologic DMARD monotherapy MTX has also been shown to improve survival The toxicities associated with MTX in the doses used in RA are very rarely lifethreatening in patients receiving recommended monitoring

44 Drug Toxicity Monitoring Methotrexate: Physical Exam: Symptoms of myelosuppression, shortness of breath, nausea or vomiting, lymph node swelling Laboratory Tests: CBC, aminotransferases & creatinine every month for the first 3 months or after increasing the dose, every 2 month for months 3-6, then every 3 month

45 Drug Toxicity Monitoring Leflunomide: Physical Exam: Diarrhea, Alopecia, intercurrent liver, gallbladder, and renal disease, pregnancy or delayed menses Laboratory Tests: CBC, aminotransferases & creatinine every month for the first 3 months or after increasing the dose, every 2 month for months 3-6, then every 3 month

46 Oral Glucocorticoids Oral glucocorticoids to help control disease activity in the initial treatment of severely active RA Initiate therapy with prednisone 5-20 mg/day, depending upon the severity of joint inflammation (5-7.5 mg?) Glucocorticoids should then be tapered as rapidly as tolerated with the goal of further tapering and eventual discontinuation (4-6 m)

47 Notes about Glucocorticoids Taper the glucocorticoids as rapidly as tolerated once disease is controled Intraarticular injections of long-acting glucocorticoids are used to reduce synovitis Severe RA sometimes require sustained therapy with low doses of glucocorticoids (< 10 mg/day); such doses in RA are generally well-tolerated

48 Drug Toxicity Monitoring Glucocorticoids: Physical Exam: BP at each visit, polyuria, polydipsia, edema, shortness of breath, visual changes (including cataracts), weight gain Laboratory Tests: CBC, Urinalysis for glucose yearly, bone mineral density

49 Anti-Inflammatory Agents Systemic/Intraarticular glucocorticoids + NSAIDs Temporary control of disease activity in 1. Beginning of the treatment 2. Modification of treatment 3. Disease flare Why? Although NSAIDs and/or glucocorticoids act rapidly to control inflammation, they do not provide adequate benefit on longer-term control of disease or for prevention of joint injury

50 Notes about NSAIDS NSAIDs are usually better tolerated than aspirin. Because of interpatient variability in response to a given NSAID, selection has traditionally been based on cost, duration of action, and patient preference. Courses of several different NSAIDs, even those within the same chemical class, may be necessary to determine The greatest concern of NSAID therapy is the risk of serious GI bleeding Cardiovascular (HTN, HF) and renal toxicity are also important considerations

51 Drug Therapy for Flares In patients with a single or few affected joints, intraarticular glucocorticoid More widespread flares may be treated by initiating glucocorticoid therapy or oral glucocorticoid ( when controlled) With respect to background drug therapy, an escalation in dose or a modification Patients on MTX who will tolerate a slower resolution of their flare MTX or to a switch from oral to SQ/IM

52 What is Pulse Therapy Methylprednisolone Three daily infusions Up to 1000 mg Limited to severe flares With systemic manifestations (e.g. rheumatoid vasculitis)

53 Pregnancy The use of oral contraceptives appears neither to worsen nor to improve disease activity We usually (50-80%) seen improvement of RA symptoms during pregnancy ~ 90% flare during the postpartum period (first three months)

54 Medication Use During Pregnancy Moderate to high risk of fetal harm: 1. Methotrexate 2. Leflunomide Allowed during pregnancy: 1. Glucocorticoids: Prednisolone & Methylprednisolone 2. NSAIDs & Aspirin 3. TNF inhibitors

55 Medication Use During Pregnancy Minimal fetal and maternal risk 1. Hydroxychloroquine 2. Sulfasalazine

56 Medication use during breastfeeding NSAIDs can be used, but aspirin should be avoided Prednisone can be taken in low doses. In patients taking 20 mg/day, it is recommended to wait 4 h after the dose prior to nursing Azathioprine, Cyclosporine, Cyclophosphamide, Methotrexate, Chlorambucil should be avoided in nursing women

57 Biologic Agents Targeted the action of TNF-a: 1. Soluble TNF receptors with high TNF binding affinity (e.g., etanercept) 2. Antibodies against TNF-α (e.g., infliximab, adalimumab, Gulimumab, and Certolizumab Pegol) All five TNF- α inhibitors are highly effective in reducing RA disease activity Comparative trials that anyone TNF-α inhibitor is superior to another with regard to efficacy

58 Pearls Anti-infliximab antibodies can develop with the long-term use of infliximab, but these can be prevented by concomitant immunosuppression with MTX Etanercept has been shown to have a decreased incidence of reactivation of latent tuberculosis (TB) when compared with infliximab and adalimurnab Etanercept has a rapid onset of action and a short half-life, which helps guard against toxicity

59 Pearls Because no superiority of one agent versus another has been shown, choice of agent is driven by cost, insurance coverage Biologic agents should not be given to patients with active infection Anti-TNF therapy is not recommended for RA patients with moderate to severe (NYHA class III and IV) heart failure Can be used with caution in patients with mild (NYHA class I and II) heart failure, but patients should be closely monitored for cardiac decompensation

60 IL-1 RA TNF-a seems to be key in RA inflammation Regulation and symptomatology, IL-l may be largely responsible For bony erosion and periarticular osteoporosis Anakinra is a recombinant form of nonglycosylated human IL-l Ra Anakinra is approved for the treatment of moderately to severely active RA in patients who have failed one or more DMARDs

61 Non-TNF biologic agents Available for RA patients who have not responded to at least one DMARD are Abatacept, RXB Each of these agents possesses a novel mechanism of action targeting either T cells, B cells Abatacept is approved as a first-line biologic along with the TNF-a inhibitors RXB are indicated only after the failure of one or more TNF-a inhibitors

62 Abatacept It is a selective costimulation modulator that inhibits t-cell activation Abatacept is generally safe All infections (54% vs. 48%) and serious infections (3.0% vs. 1.9%) occurred at a slightly higher rate among abatacept-treated versus placebo-treated patients The most common abatacept-associated serious infections included pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis. Overall risk of malignancy seems to be no different than with placebo

63 The End