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Tetracyclines should not be prescribed for children younger than 9 years of age

because of potential impairment of bone growth and discoloration of forming teeth.

Pregnant women must avoid tetracyclines because of bone growth effects on the fetus.

Minocycline is sometimes tried if other tetracyclines fail, but is more expensive and

not clearly better in efficacy, even in resistant acne. It is also associated with a

higher rate of serious adverse effects than other tetracycline antibiotics.

30

Trimethoprim/sulfamethoxazole is also effective, but has a less favorable adverse

effect profile when compared to tetracycline. It is reserved for situations when other

antibiotics are unable to be used.

16

In patients who are unable to take oral antibiotics

mentioned above (including pregnant patients), erythromycin may be an option

despite association with higher rates of resistance.

Most oral antibiotics are given twice daily for a 3-month course, followed by

continuation of a topical retinoid for maintenance therapy.

23

Oral Antibiotics

Oral antibiotics should not be used as monotherapy. Benzoyl peroxide may be added

for patients with maculopustular or nodule acne. If lesions are widespread or

difficult to reach, oral antibiotics are generally preferred over topical agents. They

are also used as a step-up therapy when topical antibiotic regimens fail to suppress

acne.

Antibiotic Resistance

Antibiotic resistance of P. acnes is increasing and correlates with prescribing

patterns. Erythromycin has the highest rate of resistance. Resistance to tetracyclines

is less common and is increasing at a slower rate than resistance to other antibiotics.

In an effort to minimize resistance, guidelines increasingly emphasize that antibiotics

should be reserved for acne of at least maculopapular subtype. Antibiotics should be

used with drugs exerting additional mechanisms of action, ideally topical retinoids,

rather than used as monotherapy, and should be used for the shortest effective

duration to obtain acne control (trials to stop antibiotics every 3 months). Antibiotics

should not be used for maintenance of control (rather, the retinoid should be

continued for maintenance). Including benzoyl peroxide in regimens containing

antibiotics reduces the development of resistance, and it is particularly recommended

if antibiotic therapy needs to be continued beyond 3 months to maintain control.

21

If

adherence to therapy with an antibiotic and both topical retinoid and leave-on

benzoyl peroxide formulations is challenging, even a benzoyl peroxide wash product

can be helpful.

31,32 Dual antibiotic use is inappropriate because it increases the risk

of bacterial resistance without offering therapeutic gain, as bacterial eradication is

not a therapeutic goal.

BENZOYL PEROXIDE

Benzoyl peroxide is another effective agent for those with maculopustular acne. It

works through three mechanisms: antimicrobial,

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anti-inflammatory, and keratolytic effects. It is important to note that there is no

reported resistance of P. acnes to benzoyl peroxide. Benzoyl peroxide is available

over-the-counter and by prescription in a variety of dosage forms. It is important to

be aware that benzoyl peroxide inactivates some formulations of tretinoin, so they

should not be used together, or should at least be applied at different times (morning

and evening, respectively).

33 However, benzoyl peroxide can be used in combination

with either adapalene or tazarotene to provide additive benefit. Benzoyl peroxide is

usually applied to the affected area once or twice daily. The most common adverse

effects of benzoyl peroxide include contact dermatitis (occurs in up to 2.5% of

patients), erythema, peeling, and skin drying.

27 Those who develop contact dermatitis

should be instructed to stop. Patients should be counseled to be careful when

applying this medication because it can bleach hair and dyed fabrics.

CASE 40-3

QUESTION 1: R.P. is an 18-year-old male who has had acne since his early teens. He started out with

comedonal acne alone, but now has a number of inflammatory pustules across his forehead and nose. Upon

further examination, you can also see that he has dry skin with numerous comedones on his chin. R.P. was

prescribed tretinoin 0.1% gel in the past, but he stopped this due to skin irritation and dryness. He has been

using salicylic acid washes daily, without success. What changes to R.P.’s medication regimen do you

recommend?

Guidelines currently recommend topical retinoids as a cornerstone of therapy for

patients with comedonal and inflammatory acne. Although R.P. had been unable to

tolerate tretinoin gel in the past, it may have been secondary to the vehicle and

strength of the medication that he was prescribed. Gels tend to dry out the skin and

are not the preferred vehicle for patients like R.P. who have dry skin. Recommend

that R.P. restarts a topical retinoid with a cream or lotion formulation. You could

also recommend that he starts with a lower strength tretinoin for tolerability

(available in strengths as low as 0.02%). Because R.P. also presents with pustules,

he could also start on a topical antimicrobial agent such as a topical antibiotic or

benzoyl peroxide.

CASE 40-3, QUESTION 2: One year later, R.P. returns to the pharmacy and reports that his acne therapy is

“not working.” He saw his dermatologist and has been using clindamycin lotion 1% every morning, adapalene

cream 0.1% every night, and benzoyl peroxide lotion 4% daily for the past year. Upon examination, you can

notice that he continues to have maculopapular acne in addition to a few nodules. What changes do you

recommend to his treatment regimen?

R.P. should stop his topical antibiotic and start an oral antibiotic, such as

doxycycline. If he is able to tolerate doxycycline, he should continue this medication

for 6 to 8 weeks, at which point changes should be made if there is no

improvement.

34,35

If the response is adequate, R.P. should try to stop doxycycline

after 3 months. Topical retinoid therapy and benzoyl peroxide should be continued

during doxycycline therapy and then after the antibiotic course to maintain treatment

benefit. If R.P. were to experience a treatment relapse in the future, after successful

use of an oral antibiotic, another course of the same antibiotic should be used;

switching antibiotics offers no therapeutic benefit and can promote multidrug

resistance.

31 With only a few nodules present, it is not appropriate to initiate oral

isotretinoin without adequate trials of other treatment options.

CASE 40-4

QUESTION 1: M.J. is a 24-year-old female who presents to the clinic with maculopapular acne. She reports

that her acne typically worsens 1 week before her menstrual cycle and improves once menses begins. She says

that she is tired of applying all of these creams and is looking for an alternative way to manage her acne. What

treatment options would you recommend for her?

HORMONAL THERAPIES

Hormonal therapies with antiandrogenic effects, such as androgen receptor

antagonists and combination oral contraceptives, are the only treatments besides oral

isotretinoin to attack acne by reducing sebum production. Hormonal therapies may be

helpful in patients with normal serum androgen levels, as well as in patients with

elevated serum androgen levels, because hypersensitivity to androgens sometimes

occurs at the follicular level despite normal circulating androgen levels.

32 These

treatments are good options for women with acne who are not pregnant, for those

who desire contraception, and for women with polycystic ovary syndrome or other

hyperandrogenic conditions or symptoms.

32 Systemic effects of hormonal therapy

generally preclude their use in male patients. Response to hormonal therapies can

take 3 to 6 months because their mechanism of action, reducing sebum production, is

an early step in the cascade of acne pathology.

36

Androgen Receptor Antagonists

Spironolactone at doses of 25 to 100 mg/day reduces acne because it is an androgen

receptor antagonist and inhibits 5-β-reductase. Tolerability and serum potassium

should be monitored every 3 weeks until maximum tolerated dose or 100 mg/day is

achieved, titrating in 25-mg increments. Spironolactone is generally well tolerated,

although gynecomastia, menstrual irregularities, and hyperkalemia are possible.

32

Female patients should use contraception because of the potential for antiandrogen

exposure to impair the sexual development of male fetuses. Spironolactone should be

used with caution in male patients given the risk for gynecomastia and possibly lower

efficacy when compared to female patients.

37

Combination Oral Contraceptives

Estrogen, usually administered as ethinyl estradiol in a combination oral

contraceptive, improves acne in females by reducing ovarian androgen production

and by increasing sex hormone-binding globulin concentrations in the serum, thereby

lowering free testosterone levels. The manufacturers of Ortho Tri-Cyclen, Gianvi,

Loryna, Nikki, Vestura, Estrostep, and Yaz specifically sought and obtained FDA

approval for acne indications. Studies of combination oral contraceptives containing

levonorgestrel, norethindrone acetate, drospirenone, dienogest, nomegestrol,

cyproterone acetate, desogestrel, or gestodene (not available in the United States)

have demonstrated efficacy in acne.

38 Comparative trials have not yet clearly

established clinically significant superiority of one product over another.

38

In

individual patients, products containing progestins with androgenic effects (e.g.,

norgestrel, levonorgestrel) may override the effect of ethinyl estradiol and worsen

acne. Conversely, patients already on a combination oral contraceptive may improve

when switched to a formulation with a less androgenic progestin (norgestimate,

desogestrel).

39 Other estrogen-containing contraceptives (transdermal patches,

vaginal rings) may have similar beneficial effects to combination oral contraceptives,

but studies have not been conducted.

If M.J. is not interested in becoming pregnant in the near future, hormonal therapy

may be a good option for treatment of her acne. Because the onset of hormonal

therapy is delayed, she

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should be counseled to continue using her current treatments for at least 3 months.

At that time, she may try stopping her topical treatments and continuing hormonal

therapy as an acne monotherapy.

NODULAR ACNE CASE

CASE 40-5

QUESTION 1: K.S. is a 24-year-old female who first noticed acne when she was 10 years old. As a teen,

she used topical benzoyl peroxide, topical adapalene, and systemic erythromycin with limited success. Two

years ago, she was diagnosed with polycystic ovary syndrome and began taking Ortho Tri-Cyclen along with

her maintenance adapalene treatment, after which her acne improved, but was not eradicated. Ten months ago,

she also began taking minocycline 100 mg orally twice daily. After a few months, she experienced significant

improvement, but she has not been able to stop antibiotics because of recurrent flare-ups. She now has at least

a dozen nodules widely distributed among multiple papules and pustules on her face and back. What

pharmacologic therapy would you recommend for K.S.?

Pharmacotherapy

ORAL ISOTRETINOIN

Isotretinoin (Absorica, Amnesteem, Claravis, Myorisan, Zenatane) is the only agent

effective for the treatment of nodular acne largely in part due to its mechanism of

action. It exhibits all four of the mechanisms of action currently used to attack acne,

making it a uniquely effective monotherapy. It is administered by mouth as 10-, 20-,

30-, and 40-mg capsules. In most cases, one or two 5-month-long courses of therapy

will induce a remission lasting for several months or even years after the drug is

stopped. Although this medication is very effective in the suppression of acne, it is

not utilized in more mild cases of acne due to its adverse effect profile. It should be

reserved as a last-line therapy for patients with nodular acne and those variants of

acne that are prone to scaring.

The most effective medication for K.S. will be oral isotretinoin at an initial dose

of 20 mg twice daily (targeting 0.5 mg/kg/day). The dosage should be increased to 40

mg twice daily (1 mg/kg/day) as tolerated after 1 month. The dose should be divided

twice daily and given with food. For best results and minimal risk of relapse,

treatment should be continued until a cumulative dose of approximately 120 mg/kg is

reached, usually about 5 months.

33 Higher dosages are associated with an increased

risk of adverse effects. K.S. should stop taking minocycline when isotretinoin therapy

begins because isotretinoin is effective monotherapy, and coadministration of

isotretinoin and tetracyclines increases the risk of intracranial hypertension.

34

Adapalene is also unnecessary once isotretinoin begins. Her acne should

significantly improve within the first month of therapy and gradually resolve by the

third or fourth month. A second course of therapy is usually not necessary.

CASE 40-5, QUESTION 2: K.S.’s prescriber discusses enrolling her in iPLEDGE. What is the iPLEDGE

program? What should K.S. know about avoiding pregnancy while taking isotretinoin?

Isotretinoin is severely teratogenic.

40 A Food and Drug Administration-mandated

Risk Evaluation Mitigation Strategy (REMS) strict risk management program called

iPLEDGE regulates the prescription and distribution of isotretinoin in the United

States.

41 The program requires all patients, prescribers, pharmacies, and even drug

wholesalers involved in distribution and use of the drug to register with a national

database. Proper patient monitoring and education, including negative pregnancy tests

in female patients of childbearing potential, must be documented in the database each

month before initial or refill medication can be dispensed to a patient. Because of the

teratogenicity or oral isotretinoin, patients (both male and female) should also be

counseled not to donate blood during therapy and for at least a month after therapy, to

ensure no pregnant woman receives isotretinoin-contaminated blood products.

Female patients of childbearing potential must use two forms of contraception for

at least a month before, during, and a month after isotretinoin therapy. At least one

contraception method must be a “primary” method. K.S. is already using an approved

primary method with Ortho Tri-Cyclen; approved primary methods also include

bilateral tubal ligation, partner’s vasectomy, some intrauterine devices, or hormonal

methods (other than progestin-only minipills). However, she must also begin using a

backup method, such as condoms. The program requires that all female patients of

childbearing potential must have two negative pregnancy tests before initiating

isotretinoin therapy, one at the time of screening and then another, from an

appropriately certified laboratory, after 1 month of using their chosen contraception

regimen. The program also requires a negative pregnancy test before each monthly

refill is prescribed, immediately after therapy, and a month after therapy. K.S. and

her prescriber will both have to verify with the program on a monthly basis that she

has been counseled again regarding contraception.

CASE 40-5, QUESTION 3: How should K.S. be counseled with regard to adverse effects of isotretinoin?

In addition to its teratogenic effects, oral isotretinoin can also cause numerous

dermatologic effects including dryness, erythema, peeling and photosensitivity.

40 To

minimize this, patients should be instructed to use daily moisturizers, sunscreen and

protective clothing if going out into the sun. K.S. should also be counseled to avoid

waxing, dermabrasions and any other dermatologic procedures during and up to 6

months after the completion of treatment. Other common side effects that K.S. should

be cognizant of include hair dryness, hair thinning and nail fragility.

CASE 40-5, QUESTION 4: What laboratory testing should be performed prior to the initiation of oral

isotretinoin?

Before beginning isotretinoin therapy, all patients, both male and female, should

have the following baseline laboratory tests: a fasting lipid panel; a liver function

panel, including both serum transaminases and bilirubin; and a complete blood count,

including platelets.

40 For accurate triglyceride results, the blood sample should be

collected at least 36 hours after alcohol consumption and 10 hours after having food.

A lipid panel should be redrawn 4 and 8 weeks into isotretinoin therapy to document

the effect of the drug because 20% of patients develop significant triglyceride

elevations.

9,42 Triglyceride levels greater than 400 mg/dL should be treated with diet

and reduced alcohol intake; monthly monitoring should continue throughout

isotretinoin therapy. In the unusual event that triglyceride levels exceed from 700 to

800 mg/dL, isotretinoin should be discontinued, or continued at a reduced dosage

with concomitant gemfibrozil therapy to reduce the risk of pancreatitis.

9

If

pancreatitis develops, isotretinoin must be discontinued. Liver function tests and

blood counts only need to be redrawn during therapy if symptoms suggestive of

hepatitis or blood dyscrasias appear.

9,16

CASE 40-5, QUESTION 5: K.S. has never had problems with depression, but her prescriber completed a

psychiatric history and assessment of current symptoms, and her iPLEDGE patient education materials warn

against possible drug-induced depression. The thought of suddenly becoming violent or suicidal concerns her.

How significant is this risk?

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Isotretinoin product labeling includes a warning that isotretinoin may cause

depression, including suicide attempts, psychosis, and violent behavior. Case reports

suggest that isotretinoin causes psychiatric symptoms in some patients. Prospective

trials and literature reviews have not established a causal relationship between

isotretinoin and depressive symptoms.

43 Although the absolute risk is low, druginduced depression is a possible idiosyncratic reaction to isotretinoin in individual

patients. In any case, all patients with severe acne, whether receiving isotretinoin or

not, should be monitored for the development or worsening of depression.

16 K.S.

should be reassured that the risk of drug-induced psychiatric symptoms is low. If she

does notice any of the psychiatric symptoms listed in her medication guide, she

should contact her prescriber immediately and stop isotretinoin.

CASE 40-5, QUESTION 6: After 3 weeks of therapy, K.S. complains of dry eyes, dry skin, and cracks with

bleeding at the corners of her mouth. What do you recommend to manage these adverse effects?

K.S. should use artificial tears to relieve the discomfort of her dry eyes; if she is

still uncomfortable after several days, she can also apply lubricating ophthalmic

ointment at bedtime. She should liberally apply moisturizer to dry skin, particularly

after bathing (see Chapter 39, Dermatotherapy and Drug-Induced Skin Disorders).

Frequent application of a lip balm or emollient, ideally one containing sunscreen,

will treat cheilitis. If the symptoms become intolerable, a small reduction in the

isotretinoin dose (e.g., reduction of 10–20 mg/day) usually decreases the intensity of

skin and mucous membrane reactions. Drug discontinuation is rarely necessary.

40

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key Reference

Zaenglen AL et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016; 74: 945–

973.(16)

Key Websites

American Academy of Dermatology Clinical Guidelines. https://www.aad.org/education/clinical-guidelines.

iPLEDGE Program. https://www.ipledgeprogram.com/.

COMPLETE REFERENCES CHAPTER 40 ACNE

Tan JK et al. A global perspective on the epidemiology of acne. Br J Dermatol. 2015;172(S1):3–12.

Ghodsi SZ et al. Prevalence, severity, and severity risk factors of acne in high school pupils: a community-based

study. J Invest Dermatol. 2009;129:2136.

Mourelatos K et al. Temporal change in sebum excretion and propionibacterial colonization in preadolescent

children with and without acne. Brit J Dermatol. 2007;156:22.

Friedlander SF et al. Acne epidemiology and pathophysiology. Semin Cutan Med Surg. 2010;29(2, Suppl 1):2.

Yentzer BA et al. Acne vulgaris in the United States: a descriptive epidemiology. Cutis. 2010;86:94–99.

Nelson AM, Thiboutot DM. Biology of sebaceous glands. In: Wolff K et al, eds. Fitzpatrick’s Dermatology in

General Medicine. 7th ed. Vol. 1. New York, NY: McGraw-Hill; 2008:687.

Gollnick H. Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs. 2003;63:1579.

Kerkemeyer K. Acne vulgaris. Plast Surg Nurs. 2005;25:31.

Zaenglein AL et al. Acne vulgaris and acneiform eruptions. In: Wolff K, et al. Fitzpatrick’s Dermatology in

General Medicine. 7th ed. Vol. I. New York, NY: McGraw-Hill; 2008:690.

Burkhart CN, Burkhart CG. Microbiology’s principle of biofilms as a major factor in the pathogenesis of acne

vulgaris. Int J Dermatol. 2003;42:925.

Williams HC et al. Acne vulgaris. Lancet. 2012;379:361–372.

Magin P et al. A systematic review of the evidence for ‘myths and misconceptions’ in acne management: diet,

facewashing, and sunlight. Fam Pract. 2005;22:62.

Spencer EH et al. Diet and acne: a review of the evidence. Int J Dermatol. 2009;48:339.

Archer CB et al. Guidance on the diagnosis and clinical management of acne. Clin Exp Dermatol. 2012;37(1):1–

6.

Chen W et al. Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad

Dermatol Venereol. 2011;25:637–646.

Zaenglen AL et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945–

973.

Eichenfield LF et al. Evidence based recommendations for the diagnosis and treatment of pediatric acne.

Pediatrics. 2013;131(S3):S163–S168.

Gollnick H et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am

Acad Dermatol. 2003;49(1 Suppl):S1–S31.

Du-Thanh A et al. Drug-induced acneiform eruption. Am J Clin Dermatol. 2011;12(4):233–245.

Rivera AE. Acne scarring: a review and current treatment modalities. J Am Acad Dermatol. 2008;59:659.

Gamble R et al. Topical antimicrobial treatment of acne vulgaris: an evidence-based review. Am J Clin Dermatol.

2012;13(3):141–152.

Davis EC, Callender VD. Postinflammatory hyperpigmentation. J Clin Aesthet Dermatol. 2010;3(7):20–31.

Kosmadaki M, Katsambas S. Topical treatments for acne. Clin Dermatol. 2017;35(2):173–178.

Zaenglein AL. Topical retinoids in the treatment of acne vulgaris. Sem Cutan Med Surg. 2008;27:177–182.

Thiboutot D. Versatility of azelaic acid 15% gel in treatment of inflammatory acne vulgaris. J Drugs Dermatol.

2008;7:13–16.

Degitz K, Ochsendorf F. Pharmacotherapy of acne. Expert Opin Pharmacother. 2008;9(6):955–971.

Akhavan A, Bershad S. Topical acne drugs: review of clinical properties, systemic exposure, and safety. Am J

Clin Dermatol. 2003;4:473.

Eady EA et al. Is antibiotic resistance in cutaneous propionibacteria clinically relevant? Implications of resistance

for acne patients and prescribers. Am J Clin Dermatol. 2003;4:813–831.

Webster GF, Graber EM. Antibiotic treatment for acne vulgaris. Semin Cutan Med Surg. 2008;27:183.

Garner SE et al. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2012;

(8):CD002086.

Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris. Dermatol Clin. 2009;27:33.

Betolli V et al. Is hormonal treatment still an option in acne today? Br J Dermatol. 2015;172(1):37–46.

Dawson AL, Dellavalle RP. Acne vulgaris. BMJ. 2013;346:1–7.

Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic agents. Am J Clin Dermatol.

2003;4:307.

Ozolins M et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial

acne vulgaris in the community: randomised controlled trial. Lancet. 2004;364:2188.

James WD. Clinical practice: acne. N EnglJ Med. 2005;352:1463.

Sato K et al. Anti-androgenic therapy using oralspironolactone for acne vulgaris in Asians. Aesthetic Plast Surg.

2006;30(6):689–694.

Arowojolu AO et al. Combined oral contraceptive pills for treatment of Acne. Cochrane Database Syst Rev.

2012;(7):CD004425.

Katsambas AD, Dessinioti C. Hormonal therapy for acne: why not as first line therapy? Facts and controversies.

Clin Dermatol. 2010;28:17.

Layton A. The use of isotretinoin in acne. Dermato Endocrinol. 2009;1(3):162–169.

iPLEDGE: Committed to Pregnancy Prevention. https://www.ipledgeprogram.com/. Accessed August 18,

2015.

Kaymak Y, Ilter N. The results and side effects of systemic isotretinoin treatment in 100 patients with acne

vulgaris. Dermatol Nurs. 2006;18:576.

Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic

review. Semin Cutan Med Surg. 2007;26: 210.

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Psoriasis is a chronic, proliferative skin disease that is characterized by

well-delineated, thickened erythematous skin plaques and is both topical

and systemic in nature. It is immune-mediated with both vascular and

inflammatory changes, which precede epidermal changes.

Case 41-1 (Question 1)

Precipitating factors for psoriasis include cold weather, anxiety and

stress, viral or bacterial infections, epidermal trauma, or drugs.

Case 41-1 (Questions 2,4)

Topical corticosteroids are first-line treatment for mild psoriasis because

of their prompt relief, convenience, and anti-inflammatory,

immunosuppressant, and antipruritic properties.

Case 41-1 (Question 5)

Alternative topical treatments for mild psoriasis—coal tar, anthralin,

calcipotriene, calcitriol, and tazarotene—and phototherapy are not as

convenient as topical corticosteroids, but have well-established efficacy

for initial management.

Case 41-1 (Question 6)

Treatment goals for severe psoriasis include both safe and effective

resolution of the disease and long-term maintenance using agents to

induce immunosuppressive or remittive cellular changes.

Case 41-2 (Questions 1,2)

Psoriatic arthritis can occur in up to 40% of patients with psoriasis, and

mild disease is treated first with nonsteroidal anti-inflammatory drugs

and second with an immunosuppressive agent, methotrexate.

Case 41-3 (Question 1)

Use of immunosuppressive agents can be limited as a result of adverse

effects, monitoring requirements, or toxicity. There is also a lack of

evidence to support that they modify the long-term disease process.

Immunomodulatory therapy, including T-cell agents and TNF-α

inhibitors, is thought to target the immune-mediated mechanism of