Perspectives in Primary Care: Evaluating and Managing Patients with Chronic Urticaria

Transcription

1 Saturday General Session Perspectives in Primary Care: Evaluating and Managing Patients with Chronic Urticaria Anne Marie Ditto, MD Associate Professor of Medicine Division of Allergy Immunology Northwestern University Feinberg School of Medicine Chicago, Illinois Educational Objectives By the end of this educational activity, participants should be better able to: 1. Identify signs, symptoms, and disease complications of chronic urticaria. 2. Evaluate patients with chronic urticaria for medication tolerance, efficacy, and adverse effects. 3. Use communication strategies to educate patients with chronic urticaria about appropriate referral resources, adherence, and self monitoring for adverse effects. Speaker Disclosure Dr. Ditto has disclosed that she has received grant support from Amgen. Supporter Disclosure This CME activity is supported by an educational grant from Novartis. It has been planned and produced by North Carolina Academy of Family Physicians and Spire Learning with TAFP strictly as an accredited continuing medical education activity. 14

2 Sponsorship and Support Perspectives in Primary Care: Evaluating and Managing Patients With Chronic Urticaria This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning. Please complete the preassessment located in your meeting handout before the program begins. This activity is supported by an educational funding donation provided by Novartis Pharmaceuticals Corporation. Accreditation and Disclaimer Statements This live activity, Perspectives in Primary Care: Evaluating and Managing Patients With Chronic Urticaria, has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AMA/AAFP Equivalency: AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 Credit(s) toward the AMA Physician s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed credit, not as Category 1. Instructions to Receive Credit To receive credit for your participation in this educational activity: Read the objectives and other introductory CME information Complete the preassessment prior to the start of the activity Participate in the chronic urticaria presentation Complete the post-assessment and evaluation at the conclusion of the activity If you are seeking Prescribed credit, you must complete the post-assessment and evaluation form at the conclusion of the activity. Activity Chair Jonathan A. Bernstein, MD Professor of Clinical Medicine Department of Internal Medicine Division of Immunology/Allergy Section University of Cincinnati Medical Center Cincinnati, OH Faculty and Disclosures Disclosure Statement Dr. Bernstein has disclosed the following relationships: Research, Consulting, and Speaker: CSL Behring; Genentech, Inc; Novartis Pharmaceuticals Corporation; Shire PLC Research and Consulting: Pharming Group Faculty and Disclosures (Cont d) Faculty Anne Marie Ditto, MD Associate Professor of Medicine Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Chicago, IL Disclosure Statement Dr. Ditto has nothing to disclose with regard to commercial support. 1

3 Faculty and Disclosures (Cont d) Faculty David A. Khan, MD Professor of Medicine and Pediatrics Division of Allergy and Immunology University of Texas Southwestern Medical Center Dallas, TX Disclosure Statement Dr. Khan has disclosed the following relationship: Speaker/Honoraria: Genentech, Inc. Faculty and Disclosures (Cont d) Faculty David M. Lang, MD Professor of Medicine Chair, Department of Allergy and Clinical Immunology Co-director, Cleveland Clinic Asthma Center Director, Allergy/Immunology Fellowship Cleveland Clinic Respiratory Institute Cleveland, OH Disclosure Statement Dr. Lang has disclosed the following relationships: Consulting and Research: Genentech, Inc; Merck; Novartis Pharmaceuticals Corporation Financial Interest/Affiliation: AstraZeneca; GlaxoSmithKline; Hycor Biomedical Agenda 5 minutes Welcome and Introductions 10 minutes CU: Making the Diagnosis 10 minutes Step-care Approach to the Management of CU 10 minutes Tailoring CU Treatment Regimens 10 minutes Improving Continuity of Care for Patients With CU 10 minutes Q & A 5 minutes Post-assessment/Evaluation Strength of Recommendation A Directly based on category I evidence B Directly based on category II evidence or extrapolated recommendation from category I evidence C Directly based on category III evidence or extrapolated recommendation from category I or II evidence D Directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence E Based on consensus of the Joint Task Force on Practice Parameters LB Laboratory based Levels of Evidence Category of Evidence Ia Evidence from meta-analysis of randomized controlled trials Ib Evidence from at least 1 randomized controlled trial IIa Evidence from at least 1 controlled study without randomization IIb Evidence from at least 1 other type of quasiexperimental study III Evidence from nonexperimental descriptive studies, such as comparative studies IV Evidence from expert committee reports or opinions or clinical experience of respected authorities or both Off-Label Statement The faculty intend to discuss the non FDA-approved or investigational uses of H 2 -antagonists, leukotriene receptor antagonists, high-dose antihistamines, anti-inflammatory agents (e.g., dapsone, sulfasalazine, hydroxychloroquine, colchicine) and immunosuppressant agents (e.g., cyclosporine, mycophenolate, tacrolimus) for the treatment of chronic urticaria. Participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this activity. Learning Objectives At the conclusion of this live activity, family physicians should be able to: IDENTIFY signs, symptoms, and disease complications of chronic urticarial. EVALUATE patients with chronic urticaria for medication tolerance, efficacy, and adverse effects. USE communication strategies to educate patients with chronic urticaria about appropriate referral resources, adherence, and self-monitoring for adverse effects. 2

4 Goals Perspectives in Primary Care: Evaluating and Managing Patients With Chronic Urticaria Define the differences between acute and chronic urticaria Determine the diagnostic features of chronic urticaria Determine the appropriate evaluation of chronic urticaria Discuss the optimal therapeutic approach to patients with chronic urticaria Clinical Features: Urticaria Repeated occurrence of evanescent cutaneous wheals accompanied by erythema and pruritus Wheals range in size from a few millimeters to > several centimeters Wheals may be scattered or coalesce into larger hives Individual wheals typically last less than 24 hours Lesions should resolve without any residual marks Case Report 1 A 33-year-old male develops raised, erythematous, pruritic lesions on his trunk and arms while outdoors at a picnic He recalls feeling a burning sensation in his foot while walking barefoot in the grass He denies any difficulty breathing, abdominal symptoms, or lightheadedness He takes diphenhydramine and his symptoms resolve in 45 minutes Photos not available for handout. Urticaria Classification Acute urticaria: Lasts <6 weeks Affects as many as 20% of the population at some point in their lives Episodes are typically brief (hours-days) Etiology identified in 15% to 20% of cases May represent a symptom of many diseases rather than a unique disorder Can be accompanied by angioedema Acute Urticaria Acute urticaria is frequently a symptom of other allergic diseases involving IgE sensitization Food allergy, stinging insect allergy, drug allergy In patients with IgE-mediated urticarial reactions, the potential for multiorgan anaphylaxis exists Use of epinephrine as well as a prescription for self-injectable epinephrine should be considered for IgE-mediated acute urticaria For acute urticaria without an identifiable cause, it frequently is selflimiting and does not progress to a systemic reaction Champion RH, et al. Br J Dermatol. 1969;81: Gaig P, et al. J Investig Allergol Clin Immunol. 2004;14: IgE, immunoglobulin E. 3

5 Causes of Acute Urticaria Case Report 2 Cause IgE-mediated reaction Infection Physical factors Non-IgE-mediated reactions Toxins Other diseases Contact reactions Immune complex reactions Unknown Example Foods, insect stings, medications Epstein-Barr virus Dermographism, cold, exercise, solar, pressure Opiates Scombroid poisoning Prelude to chronic urticaria Stinging nettle Serum sickness Idiopathic acute urticaria 47-year-old woman presents with hives for 3 years Not controlled on cetirizine 10 mg, fexofenadine 180 mg, and montelukast 10 mg daily On most days 25% of her body is covered in hives with only a 50% improvement in pruritus Without medicine she cannot function due to constant itching No specific triggers for urticaria; past medical history and review of systems are otherwise negative Photos not available for handout. Urticaria Classification Chronic urticaria: Lasts >6 weeks Lesions occur several days/weeks or daily May last months to years Identifiable cause is usually unknown (idiopathic) <5% of patients had a definite cause 1,2 IgE-mediated allergy to foods or drugs is rarely identified as a cause of CU Can be accompanied by angioedema Considered a primary disease Does not progress to anaphylaxis CU, chronic urticaria. 1. Quaranta JH, et al. Ann Allergy. 1989;62: Kaplan AP. Urticaria and Angioedema. New York: Churchill Livingstone; Chronic Urticaria Prevalence estimated to be between 0.6% to 5% 1-3 No clear prevalence data in the U.S. More common in young adults to middle-aged individuals 1 More common in females Gaig, P, et al. J Investig Allergol Clin Immunol. 2004;14: Jiamton S, et al. J Med Assoc Thai. 2003;86: Vázquez Nava F, et al. Rev Allerg Mex. 2004;51: Cause Unknown Causes of Chronic Urticaria Autoantibody-associated Physical factors Infection Systemic diseases Cryopyrinopathies Example Idiopathic Thyroperoxidase antibody-associated, rheumatoid factor, anti-igg to FcER1 alpha subunit Cold, dermographism, solar, pressure, exercise, cholinergic Parasites Thyroid dysfunction Familial cold autoinflammatory syndrome Angioedema Angioedema (tissue swelling) occurs in ~40%-50% of cases of urticaria Presence of angioedema does not aid in classification, diagnosis, or treatment of urticaria Angioedema in the absence of urticaria Can be histaminergic (mediated by histamine) or non-histaminergic (mediated by bradykinin) Non-histaminergic can be acquired vs. hereditary C1 esterase inhibitor deficiency syndromes (e.g., hereditary angioedema) Acquired angioedema ACE-inhibitor angioedema IgG, immunoglobulin G. 4

6 Angioedema Clinical Features of Angioedema Swelling of deeper dermal tissue Most frequently on face, eyes, tongue, and lips Photos not available for handout. May be asymmetric Is often nonpruritic Swelling typically lasts 24 to 48 hours Diagnostic Evaluation of Acute Urticaria and Angioedema Diagnostic Evaluation of Acute Urticaria and Angioedema History and physical examination are essential to determine if additional tests are required Extensive laboratory evaluation if not supported by the history and physical examination is not recommended Limited nonspecific laboratories can be considered (e.g., CBC with diff, ESR, CRP) If an allergic etiology is suspected (e.g., food, insect, drug) then testing for specific IgE is warranted Skin testing can be performed after resolution of urticaria and discontinuation of antihistamines, otherwise serum-specific IgE testing should be utilized CBC with diff, complete blood count with differential. CRP, C-reactive protein. ESR, erythrocyte sedimentation rate. History and Physical Examination of CU Diagnostic Evaluation of Acute and Chronic Urticaria and Angioedema How Many and What Tests Are Required? Onset (e.g., timing of symptoms with any change in medication or other exposures) Frequency, duration, severity, and localization of wheals and itching Dependence of symptoms on the time of day, day of the week, season, menstrual cycle, or other pattern Known precipitating factors of urticaria (e.g., physical stimuli, exertion, stress, food, medications) Relation of urticaria to occupation and leisure activities Associated angioedema, systemic manifestations (headache, joint pain, gastrointestinal symptoms, etc.) Known allergies, intolerances, infections, systemic illnesses, or other possible causes Family history of urticaria and atopy Degree of impairment of quality of life Response to prior treatment Physical examination 5

7 Testing for Physical Urticaria A detailed history is essential in determining physical triggers suggestive of a diagnosis of physical urticaria The individual lesions of many physical urticarias are brief ( minutes) Some physical urticarias are characterized by different lesions Linear lesions (e.g., dermographism) Small punctate lesions (e.g., cholinergic, aquagenic) Tests to Confirm Physical Urticaria Physical Urticaria Diagnostic Test Cold Ice cube test Localized Heat Test tube water 42ºC Exercise for 15 to 20 minutes Cholinergic Leg immersion in 42ºC bath Delayed Pressure Sand bag test: 15 lb. weight for 10 or 15 minutes Dermographism Stroking skin Solar Specific wavelength light exposure Aquagenic Water compress Vibratory Vortex for 4 minutes Tests for Autoantibodies in CU Skin tests Autologous serum skin test Autologous plasma skin test Commercially available in vitro tests CU Index (IBT Labs) 1 Measures histamine release from donor basophils activated by patient sera IGERAB (National Jewish Labs) 2 Measures CD203c by flow cytometry on donor basophils activated by patient sera Issues With Autoantibody Testing Autologous serum skin tests do not consistently correlate with in vitro tests False positives and false negatives with ASST and in vitro tests May represent an epiphenomenon Whether detection of autoantibodies identifies a clinically unique population or will lead to a change in management is unclear 1. Biagtan MJ, et al. J Allergy Clin Immunol. 2011;127: National Jewish Health. anti-ige-receptor-ab. Accessed July 5, ASST, autologous serum skin tests. Thyroid Laboratory Testing in CU A significant proportion of CU patients have elevated levels of thyroid autoantibodies, but are euthyroid Evidence for the efficacy of thyroxine treatment of these euthyroid patients is mixed There are no large, blinded, placebo-controlled trials of thyroxine for CU Classic Cutaneous Features of Urticarial Vasculitis Urticaria description Painful, tender, burning, or pruritic Duration of lesions hours Lesions may resolve as purpura or hyperpigmentation These classic features may represent the minority of patients Photo not available for handout. 6

8 Urticarial Vasculitis Retrospective study of 312 CU patients unresponsive to antihistamines who all underwent skin biopsies Urticarial vasculitis was identified in 15.1% of patients Wheal duration lasted <24 hours in 57% of patients Purpura occurred in only 13% of patients Pain was present in <10% of patients Skin biopsy can be considered when vasculitis is suspected Laboratory Testing in Hereditary and Acquired Angioedema Table not available for handout. Please see the following reference: Khan DA. Allergy Asthma Proc. 2011;32:1-10 Tosoni C, et al. Clin Exp Dermatol. 2009;34: AAE, acquired angioedema. ACEi, ACE inhibitor-induced angioedema. C1-INH, C1 esterase inhibitor. HAE, hereditary angioedema. N, normal. Khan DA. Allergy Asthma Proc. 2011;32:1-10. Laboratory Testing for Chronic Urticaria Systematic review of 29 studies involving 6462 chronic urticaria patients concluded that the evidence highly supports avoiding routine laboratory screening 1 Subsequent retrospective study of 356 chronic urticaria patients found: 2 17% of 1872 laboratory tests were abnormal 30 patients required additional workup CBC, metabolic panels, ESR, and TSH did not result in improved patient outcome 1/356 patients (0.3%) benefited from laboratory testing TSH, thyroid-stimulating hormone. 1. Kozel MM, et al. J Am Acad Dermatol. 2003;48: Tarbox JA, et al. Ann Allergy Asthma Immunol. 2011;107: Recommendations From International Guidelines on Chronic Urticaria US Practice Parameters 1 After a thorough history and physical examination, no diagnostic testing may be appropriate for patients with CU; however, limited routine lab testing may be performed to exclude underlying causes. Targeted lab testing based on clinical suspicion is appropriate. Extensive routine testing for exogenous and rare causes of CU, or immediate hypersensitivity skin testing for inhalants or foods, is not warranted EAACI/GA 2 LEN/EDF/WAO Guidelines 2 Very limited routine diagnostic measures (CBC w/diff, ESR or CRP) for chronic spontaneous urticaria (strong recommendation/clinical consensus) Zuberbier T, et al. Allergy. 2014;69:e1-e29. EAACI Treatment Algorithm not available for handout. Please see the following reference: Zuberbier T, et al. Allergy. 2014;69: European vs. US Treatment Guidelines US Treatment Algorithm Step 4 Add an alternative agent Omalizumab or cyclosporine Other anti-inflammatory agents, immunosuppressants, or biologics Step 3 Dose advancement of potent antihistamine (e.g., hydroxyzine or doxepin) as tolerated Step 2 One or more of the following: Dose advancement of second-generation antihistamine used in Step 1 Add another second-generation antihistamine Add H 2-antagonist Add leukotriene receptor antagonist Add first-generation antihistamine to be taken at bedtime Step 1 Monotherapy with second-generation antihistamine Avoidance of triggers (e.g., NSAIDs) and relevant physical factors if physical urticaria/angioedema syndrome is present Begin treatment at step appropriate for patient s level of severity and previous treatment history At each level of the step-approach, medication(s) should be assessed for patient tolerance and efficacy Step-down in treatment is appropriate at any step, once consistent control of urticaria/angioedema is achieved H 1 -Antagonists: US Recommendations Effective, but not all patients achieve complete control (C) Second-generation antihistamines are first-line agents (A) Higher doses of second-generation antihistamines might provide more efficacy, but data are limited (B) First-generation and second-generation antihistamines have similar efficacies, but sedation and impairment are greater with first-generation antihistamines, especially with short-term use (A) First-generation antihistamines can be considered in patients who do not achieve control with higher-dose, second-generation antihistamines (D) Hydroxyzine or doxepin can be considered in patients whose symptoms are poorly controlled with dose advancement of second-generation antihistamines and the addition of H 2 -antihistamines, first-generation H 1 -antihistamines at bedtime, and/or antileukotrienes (D) Reprinted from J Allergy Clin Immunol, Vol 133, JA Bernstein, et al. The diagnosis and management of acute and chronic urticarial: 2014 update. P Copyright 2014, with permission from Elsevier. 7

9 Zuberbier T, et al. Allergy. 2014;69: H 1 -Antagonists: European Recommendations Second-generation H 1 -antihistamines can be used as first-line treatment (strong recommendation/high level of evidence) 4-fold dose of second-generation H 1 -antihistamines can be used as second-line treatment Second-generation H 1 -antihistamines should be taken continuously at lowest necessary dose vs on demand (strong recommendation/high-quality evidence) Second-generation H 1 -antihistamines are preferred over first-generation H 1 - antihistamines (strong recommendation/high level of evidence) Updose second-generation H 1 -antihistamines (strong recommendation/highquality evidence) up to 4X vs combining different H 1 -antihistamines (strong recommendation/low-quality evidence) H 2 -Antagonists US Guidelines A combination of H 2 -antihistamines with first- and second-generation H 1 - antihistamines are more efficacious than H 1 -antihistamines alone (A) Additional efficacy might be related to pharmacologic interactions and increased blood levels of first-generation antihistamines (B) H 2 -antagonists can be added when CU is not optimally controlled with second-generation antihistamine monotherapy (D) European Guidelines Not recommended Zuberbier T, et al. Allergy. 2014;69: Leukotriene-Modifying Agents US Guidelines Shown to be effective in several, but not all, randomized controlled studies (A) Generally well tolerated (A) Can be considered for patients with unsatisfactory responses to secondgeneration antihistamine monotherapy European Guidelines Suggested as add-on therapy to second-generation H 1 -antihistamines (weak recommendation/low level of evidence) Step 4 Alternative Therapies: US Guidelines Anti-inflammatory agents (e.g., dapsone, sulfasalazine, hydroxychloroquine, colchicine) Limited evidence for efficacy, some require laboratory monitoring for adverse effects (C) Generally well tolerated, may be considered for patients with antihistaminerefractory CU (D) Immunosuppressant agents (e.g., cyclosporine) Studied in several randomized controlled trials Weak recommendation for its use for CUA refractory to conventional treatment due to study limitations, potential harms, and cost (A) Zuberbier T, et al. Allergy. 2014;69: CUA, chronic urticaria and angioedema. Evidence for Therapies in Chronic Urticaria Laboratory Monitoring of Alternative Agents for Refractory Chronic Urticaria Table not available for handout. Please see the following reference: Khan DA. In: Maibach HI, Gorouhi F eds. Evidence Based Dermatology 2 nd ed Available at Table not available for handout. Please see the following reference: Bernstein JA, et al. J Allergy Clin Innunol. 2014;133: *Require laboratory monitoring which would increase costs Khan DA. In: Maibach HI, Gorouhi F eds. Evidence Based Dermatology 2 nd ed

10 Omalizumab US Guidelines Use is supported by large double-blind, randomized controlled trials Low rate of clinically significant adverse effects Consider for refractory CU after considering potential benefits and harms, costs, and patient s values and preferences (A) European Guidelines Recommended as add-on therapy to second-generation H 1 - antihistamines (strong recommendation/high level of evidence) Zuberbier T, et al. Allergy. 2014;69: Omalizumab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria Figure not available for handout. Please see the following reference: Mauer M, et al. N Engl J Med. 2013;368: Issues Pertaining to Omalizumab Good safety profile 1-3 Administered subcutaneously 4 Risk of anaphylaxis requires administration in physician s office 4 Mechanism of action unknown 1 Optimal duration of therapy is still unclear No validated biomarkers predicting response Patient selection does burden of disease warrant the cost of omalizumab over time? 5 Cost may be counterbalanced by lower rates of health service utilization and indirect medical expenditures due to improved quality of life and fewer flares of CU over time 5 1. Maurer M, et al. N Engl J Med. 2013;368: Saini S, et al. J Allergy Clin Immunol. 2011;128: Maurer M, et al. J Allergy Clin Immunol. 2011;128: US FDA CDER. Omalizumab BLA Label 07/06/ Other Recommendations: Special Populations European Guidelines Same treatment recommendations for children and pregnant and lactating women US Guidelines No specific recommendations Oral Corticosteroids Should be used sparingly to control acute hives (10-14 day course) in conjunction with preventive medications (H 1 /H 2 antihistamines) For chronic hives that are not responsive to step 1 and 2 treatment recommendations, short courses may be required until step 4 therapies have been initiated and have time to take effect Zuberbier T, et al. Allergy. 2014;69: Zuberbier T, et al. Allergy. 2014;69: Case Report 2: Treatment Recommendations Treatment options: Add H 2 -antihistamine Increase H 1 -antihistamine to 4X the recommended dose (i.e., fexofenadine 360 mg twice a day) Consider changing fexofenadine bedtime dose to doxepin mg at bedtime If not effective, refer to a urticaria specialist Educate patients that it is not appropriate to perform allergy skin testing to aeroallergens or foods unless they have concomitant allergic rhinitis and/or a reaction to a specific food Referrals Should refer to a urticaria specialist if patients do not respond to step 1 and 2 therapy Co-management of the patient with the specialist vs. allowing the specialist to take over the care of the patient s urticaria 9

11 Patient Education Discuss causes and triggers with patient Inform patients of medication side effects and what to watch for Emphasize the importance of taking medications on a regular basis as directed Conclusions A thorough history is essential for successful diagnosis and management of chronic urticaria Hives have characteristic physical features Therapy should follow an approved algorithmic approach Step 4 therapies include biologics, anti-inflammatory, and immunosuppressant agents Of the step 4 therapies, omalizumab has the strongest scientific evidence for treatment efficacy and safety Alternative step 4 therapies should be incorporated into treatment algorithms as appropriate because one size does not fit all Referral to a urticaria specialist is recommended if patients are not responsive to step 1 and 2 therapy Q & A Thank you Please complete the post-assessment and evaluation located in your meeting handout. 10

12 Medication Index Evaluating and Managing Patients With Chronic Urticaria The following medications were discussed in this presentation. The table below lists the generic and trade name(s) of these medications. Generic Name Cetirizine Colchicine Cyclosporine Dapsone Diphenhydramine Doxepin Fexofenadine Hydroxychloroquine Hydroxyzine Methotrexate Montelukast Mycophenolate Omalizumab Sulfasalazine Tacrolimus Trade Name Zyrtec Colcrys, Mitigare Gengraf, Neoral, Sandimmune Aczone Benadryl Silenor, Zonalon Allegra Plaquenil Vistaril Otrexup, Rasuvo, Trexall, Xatmep Singulair Cellcept Xolair Azulfidine Astagraf XL, Envarsus XR, Prograf

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