INTRODUCTION

Fiery inflammation in the bowel can be due to several conditions. In inflammatory bowel disease (IBD), gastrointestinal (GI) tract inflammation episodes are common. Crohn’s disease (CD) and ulcerative colitis (UC) are two IBDs differentiated by location and bowel involvement.¹ That’s a point to remember: that IBD is an umbrella term that includes CD and UC. In 10% to 15% of patients, the features of CD and UC are so similar that it is impossible to differentiate between them and misdiagnosis may result.^1,2 Besides the GI tract, both CD and UC also may be accompanied by symptoms outside the intestine, called extraintestinal symptoms.

 

DIFFERENTIATING CD AND UC

CD results in patchy ulceration of any portion of the GI tract (see Figure 1) from the mouth to the anus. It frequently affects the terminal ileum and colon, and bleeding is uncommon. Typically, patients experience pain in the lower right abdomen.³ UC, this continuing education’s primary focus, involves inflammation of the colon mucosa. UC often affects the rectum, referred to as proctitis, and bleeding during bowel movements is common. Typically, patients experience pain in the lower left abdomen. It may extend into the left (sigmoid) part of the pelvis or beyond the sigmoid, or include the entire colon, referred to as pancolitis.⁴ In UC, inflammation leads to edema, ulcers, bleeding, and electrolyte losses.

Figure 1. The Gastrointestinal Tract

UC is a chronic idiopathic relapsing/remitting condition (meaning it waxes and wanes) with interactions between the environment, immune system, gut microbiome, and a genetic predisposition to the disease suspected as causes.⁵  UC’s incidence and prevalence is increasing worldwide.⁶ From 1990 to 2017, its incidence increased from 3.7 million individuals to 6.8 million affected individuals worldwide.⁷ UC is incurable, so treatment goals aim to achieve rapid resolution of symptoms, mucosal healing, and clinical and endoscopic remission. An additional goal is to improve a patient’s quality of life (QoL).^6.

 

Individuals with this complex condition have a high level of disability and high healthcare resource utilization. Beyond medical management, 15% to 20% of patients with UC will require surgery. Compared to adults without IBD, adults with IBD experienced $11,029 higher direct costs per patient per year according to one report.⁸ Documenting this diagnosis in the pharmacy’s profile can help pharmacists and technicians screen for potential problems more efficiently.

 

Differentiating the two forms of IBD drives treatment. Both CD and UC present as similar repetitive episodes of GI inflammation and create significant patient burden. In CD, inflammation or ulceration commonly occurs in the ileum and colon.⁴ Outside of the intestine, CD may affect the esophagus, duodenum, or stomach, and gallstones may occur. In UC, extraintestinal manifestations may appear most commonly as inflammatory arthropathies (joint disease) and bile duct inflammation and scarring, but may include bone, eye, and skin involvement.^9,10 Although IBD’s incidence peaks at age 15 to 29 years, 10% to 15% of new diagnoses occur among adults aged 60 years or older.¹¹ Both forms of IBD are more prevalent among non-Hispanic White people than among people in other racial/ethnic groups.¹²

 

PAUSE AND PONDER: What support can you provide to a patient who tells you that wherever they go, their first action is to scan for the closest bathroom?

 

UC’S PATHOPHYSIOLOGY AND ASSESSMENT

 

The normal colon is five or six feet long and three inches wide. Its layers of circular and longitudinal muscles and tissues contract to move food and liquid forward. It wraps around the outside of the small intestine, has segments, and looks somewhat flat. A seam runs vertically down the middle so the segments bulge on either side of the seam. As UC becomes chronic, the colon becomes more rigid and short, leading to a pipe-like appearance.⁹

 

The most important risk factor for UC is a family history of IBD in a first-degree relative.¹⁴ Patients with disease extension to the left side of the colon, or extensive colitis, are more likely to need medication, undergo colectomy (removal of a portion of the colon), and develop colorectal cancer.¹⁵  Risk factors for colorectal dysplasia (abnormal that are not cancerous but can sometimes lead to cancer) or cancer include disease duration and extent, active inflammation, presence of a stricture (inelastic narrowing of a section of the GI tract), polyps, and family history of colorectal cancer. The bile duct may also become diseased in 3% to 7% of patients with UC.^15,16

 

UC’s pathophysiology involves defects in the epithelial barrier, defective immune response, the presence of leukocytes, and microflora imbalance in the colon.^17,18 UC’s inflammation deteriorates the epithelium, and exposure to certain intestinal microbes worsens the inflammation.⁹ Other immune-related factors that affect UC’s pathophysiology and the body’s response include tumor necrosis factor-alpha (TNF-alpha), numerous interleukins, and elevated immune globulin levels.¹⁷

 

Two measures are recognized in UC. Gastroenterologists and researchers tend to use the erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) components of the Truelove and Witts criteria. Researchers frequently measure ESR and CRP before and during treatments as outcome measures. The prescribing information for anti-TNFs, JAK inhibitors, and IL-12/23 antagonists also include ESR and CRP measures. Table 1 illustrates UC disease severity measured by assessment in the modified Truelove and Witts criteria.¹⁵

 

 Table 1. Modified Truelove and Witts Criteria¹⁵

Parameter	Mild	Moderate	Severe
Bloody stools/day (n)	<4	4-6	>6
Pulse (beats/minute)	<90	≤90	>90
Temperature (T) °C (T°F )	<37.5 (<99.5)	37.5 – 37.8 (99.5 – 100.4)	>37.8 (>100.4)
Hemoglobin (g/dL)	>11.5	11.5 – 10.5	<10.5
ESR (mm/hr) [or CRP mg/l]	<20 (normal)	20 – 30 (<30)	>30 (>30)

°C=degree Celsius; CRP = c-reactive protein; ESR = erythrocyte sedimentation rate; °F = degree Fahrenheit

 

In the clinical setting, the simpler Mayo score (see Table 2) is used more widely than Truelove and Witts criteria.¹⁹ It reflects stool frequency, rectal bleeding, a physician’s global assessment, and a measure of mucosal inflammation at endoscopy, with a maximum score of 12. Clinical response in UC is defined as¹⁹

• a reduction of Mayo score by at least 3 points and a decrease of 30% from the baseline score, or
• a decrease of at least 1 point on the rectal bleeding subscale or
• a total rectal bleeding score of 0 or 1

 

Table 2. Mayo Score for Ulcerative Colitis^15,20,19

	Points
Mayo Variables	0	1	2	3
Stool frequency	Normal	1-2/day more than normal	3-4/day more than normal	5/day more than normal
Rectal bleeding	None	Streaks of blood with stool <50% of the time	Obvious blood with stool most of the time	Blood passed without stool
Mucosa (endoscopic subscore)	Normal or inactive disease	Mild disease (erythema, decreased vascular pattern, mild friability)	Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)	Severe disease (spontaneous bleeding, ulcerations)
Physician’s global assessment	Normal	Mild disease	Moderate disease	Severe disease

Mayo score = sum of scores for each of the four variables (maximum score 12)

 

 

Beyond clinical response, clinical remission is a desired objective and is defined as a Mayo score of 2 or less and no individual subscore exceeding 1.¹⁹ Mucosal healing is defined as a mucosa subscore of 1 or less. Disease activity is a measure used to decide what treatments to prescribe. Mild disease activity is defined as scores of 3 to 5. Moderate and severe disease activity are defined as scores between 6 and 10 and 11 and 12, respectively.¹⁹

 

The clinician’s patient assessment must be global (all encompassing).²¹ During patient interviews, clinicians should inquire about extraintestinal symptoms, which may include joint, mood, ocular, oral, or skin changes. They should order laboratory evaluation for anemia and liver function abnormalities. Clinicians should explore QoL issues, such as impact on school, work, or personal relationships. Treatment plans should incorporate patients’ unmet needs and preferences. Exploring the need for social and emotional support, financial resources, and adequacy of patient education regarding their disease are important.²¹

 

Throughout treatment, it’s important to assess the patient’s clinical response and remission periodically. Clinicians should monitor cross-sectional imaging, specifically MRI, CT and ultrasound, and surrogate markers, such as fecal calprotectin (FCP; type of white blood cell that migrates to inflamed tissue) and CRP.^15,22 A sigmoidoscopy or colonoscopy is recommended within three to six months of initiating treatment to determine the level of suppression of the inflammation, treatment response, or the need to modify the treatment.²²

 

THE PATIENT’S JOURNEY

The journey through symptoms, diagnosis, and treatment to quell the fiery inflammation associated with UC can be long and difficult. In one study, one in four individuals with IBD reported GI symptoms to their primary care physician more than six months before receiving a diagnosis.²³ Of these individuals, 10.4% reported symptoms five years before receiving a UC diagnosis. Delayed diagnosis often results in disease progression, worsening tissue, and mucosal damage, surgery, colectomy, or colitis-associated cancer.  Patients with a previous diagnosis of irritable bowel syndrome or depression were less likely to receive a timely specialist appointment.²³

 

UC is vastly heterogeneous. Table 3 presents two cases with distinct disease journeys.

 

 

Table 3. Two Distinct Patient Journeys^24,25

UC Patient Case 1		UC Patient Case 2
9-year-old girl diagnosed after ileocolonoscopy reveals diffuse moderate inflammation		UC since age 18
Moderate clinical disease activity, Mayo score = 8		Symptoms included bleeding, severe pain and swelling in lower abdomen, gas, and nausea
Low hemoglobin, low vitamin D		Lifestyle: Undergraduate, lifeguard, swim coach
Oral corticosteroids started followed by dose tapering dose and mesalamine started		Daily regimen of oral medication, rectal suppositories, nightly enemas
At week 4, active disease remained		Symptoms worsened so → ED
IFX started at 10 mg/kg at 0, 2, and 6 weeks		Barely able to eat or drink, covered with rash and inflamed eyes
At 26 weeks with IFX, she remained in clinical remission		Incontinence in street, bus, and post office
At 1 year, she remained in remission		Acute diarrhea with each BM → became homebound
Follow-up flexible sigmoidoscopy demonstrated mucosal healing		At age 29, married → then 10 weeks of hospitalization without remission
		Agreed to surgical colectomy → difficult recovery, diarrhea, and intestinal blockages
		Finally exercising, back to work, and monitoring the quantity, texture, and timing of food. Remained on pre-surgical medications.

BM = bowel movement; ED = emergency department; IFX = inFLIXimab

 

UC affects many distinct populations. In the pediatric population with UC, unlike in adults, the clinical condition can present atypically with a more severe, early onset and continuous inflammation of the rectum and colon.^26,27,28 In these patients, clinicians should assess disease location and severity. One study indicated 62% of pediatric patients with UC from birth to age 5 years had extensive pancolitis, and 38% and 31% from ages 6 to 11 and from ages 12 to 18, respectively, had pancolitis.²⁷   Children can also experience rectal sparing (a normal/unaffected rectum) and limited distal disease.^26,28

 

To optimize management, enhance QoL, and minimize complications in all patients, continued patient engagement is important.²⁹

 

GOALS OF UC MANAGEMENT

 

The UC treatment guidelines recommend goals of therapy to include²⁹

• induction and maintenance of clinical and endoscopic remission
• maintaining steroid-free remission
• improving QoL, and
• preventing complications, hospitalizations and surgery.

Pursuing these goals can also contribute to minimizing cancer risk.^21,30,31 Long-term mucosal healing may reduce the risk of dysplasia.³¹

 

The Treat-To-Target Approach                                                         

UC is considered relapsing/remitting because it presents as relapses of symptoms and then periods of symptomless response and remission. Beyond symptom remission, a treat-to-target (T2T) approach focuses on^32,33

• minimizing disease activity
• reducing futures risks and
• reducing future relapses or complications such as ileal strictures (narrowing), fistulas, functional impairment, or colon cancer.

 

In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative recommended that UC treatment goals should address two targets: clinical and endoscopic outcomes.³² IBD experts recommend using measures of inflammation such as FCP.³²  FCP detects GI inflammation sensitively and is used to monitor disease activity and predict relapse.

 

PAUSE AND PONDER: Which UC treatments do you see in your practice location most often?

 

UC’s treatment options are plentiful and evolving. Pharmacy team members can collaborate with multidisciplinary professionals regarding patient care for UC. (See SIDEBAR). Pharmacists’ drug therapy and disease management expertise can promote individualized treatment decisions for these complex patients.

 

 

SIDEBAR: Working with the Multidisciplinary Team

Team collaboration can increase patient and provider education, enhance quality of care, and reduce disease burden, and morbidity. Many pharmacists don’t know how to introduce themselves to or work with multidisciplinary teams. Sometimes, team members from other disciplines will call with questions or concerns, and the call opens the door for regular communication. Often, however, pharmacy staff will need to take the initiative and introduce themselves. Here are four tips to working better with the UC care team.

• Ask patients if they are seeing a nutritionist, primary care provider, gastroenterologist, or behavioral health provider (for stress support). If UC is severe, inquire if they have a surgeon or know their radiologist. Record these providers’ names in the patient record and contact them when questions or concerns arise.
• Make the patient your ally and be your patient’s ally. When you educate patients well and show them your capabilities, they will report back to their clinicians.
• When you work with a patient who has UC, let the professional team members know. Sending a quick note to say that, for example, the patient’s adherence was poor and you discussed ways to improve it with the patient sheds light on possible non-response. It also makes clinicians aware that you have skills and you’re not afraid to use them!
• Don’t be afraid to make team members aware of issues like cost or availability of less expensive options. Often, prescribers have no idea that patients experience sticker shock when they fill their prescriptions.

 

TREATMENT

Medication is a mainstay of treatment for patients with UC. Prescribers may combine, dose-escalate, reduce, or discontinue medications, depending on the patient’s disease severity.

 

Traditional Treatments

When a patient presents with mild to moderate UC, the expert consensus is to start treatment with an oral 5-aminosalicylate (5-ASA; sulfasalazine, mesalamine, and diazo-bonded 5-ASA [the prodrugs, balsalazide and olsalazine, which convert to mesalamine]³⁴) with or without a rectal 5-ASA.^34,35 In many cases, rectal dosing improves symptoms; using a suppository, enema, or rectal foam applies the medication exactly where needed. Sulfasalazine, balsalazide, and mesalamine are similarly effective and safe.³⁴ Some patients will respond inadequately and may need to escalate therapy to systemic corticosteroids, immunomodulators (IMM), biologics, or other agents. If symptoms persist, it is important to rule out infection, optimize adherence, increase the oral dose, and add rectal 5-ASA if not yet prescribed.^34,35

 

Comparative efficacy studies are helpful to clinicians. One technical review of multiple drugs in mild to moderate UC compared rectal 5-ASAs (5-ASA enemas 1 to 4 g/day or 5-ASA suppositories 1g/day) to rectal corticosteroids (hydrocortisone enema 100mg/day, prednisolone enema 25–30 mg/day, budesonide enema 2 mg/day, beclomethasone 3 mg/day or comparable foam) in 13 trials.³⁶ In mild to moderate ulcerative proctosigmoiditis cases treated for two to eight weeks, rectal 5-ASAs were superior to rectal corticosteroids for induction of clinical remission.³⁶

 

Table 4 lists the broad categories of medications for mild, moderate, or severe UC and dosing information.

 

Table 4. Medications for UC^22,37-42

Category	Substance	Dosage
5 – ASA	Mesalamine     Balsalazide   Olsalazine   Sulfasalazine	2 – 4.8 g/day (oral) 1 – 2 g/day (rectal)   6.75 g/day (rectal)   1 g/day (oral)   2 – 4 g/day
Corticosteroids	Budesonide   Budesonide MMX   Prednisone   Hydrocortisone   Methylprednisolone	2 mg/day (rectal)   9 mg/day (oral)   0.75 – 1 mg/kg/day   100 mg IV 4 times/day   125 mg IV/day
Thiopurines Immunosuppressives	Azathioprine   6-mercaptopurine	2 – 2.5 (max 3) mg/kg/day   1 – 1.5 mg/kg/day
Calcineurin inhibitors	Cyclosporine   Tacrolimus	2 mg/kg/day IV   0.2 mg/kg/day
Anti-TNF agents	Adalimumab       Golimumab       Infliximab	160 mg wk 0, 80 mg wk 2, 40 mg wk 4, then 40 mg every 2 wks; may ↑ to 40 mg/wk SUBQ   200 mg wk 0, 100 mg wk 2, 50 mg wk 4, then 50 mg every 4 wks; may ↑ to 100 mg if pt>80 kg SUBQ   5 mg/kg wk 0, 2, 6, then every 8 wks IV
Adhesion molecule inhibitors (anti-integrin)	Vedolizumab	300 mg wk 0, 2, 6, then every 8 wks IV
Janus kinase inhibitor	Tofacitinib               Upadacitinib	5 – 10 mg/day (oral) First 8 wks: 10 mg twice/day 10 mg twice/day for 8 more wks if partial response Then 5 mg twice/day or 22 mg XR/day for 8 weeks; then evaluate   45 mg/day for 8 wks then 15 mg/day (oral)
Interleukin 12/23 antagonist	Ustekinumab	250 mg to 55 kg IV 390 mg if >55 kg – 85 kg IV 520 mg if >85 kg IV Then 90 mg SUBQ every 8 wks
Sphingosine 1-phosphate receptor modulator	Ozanimod	0.23 mg days 1-4, 0.46 mg days 5-7, then 0.92 mg/day (oral)

G = grams; IV= intravenous; kg=kilogram; mg= milligrams; MMX = Multi-Matrix System technology drug release; SUBQ=subcutaneous; wk= week

 

Sulfasalazine

If sulfasalazine is prescribed, 4 g provides approximately 1.6 g of 5-ASA equivalence.³⁴ Typical doses are 2 tablets 4 times a day.^37,43 In some cases, prescribers may initiate therapy with a smaller dose, (e.g., 1 to 2 g daily) to reduce possible GI intolerance and slowly increase as tolerated. They may also try enteric-coated sulfsalazine.^37,43 Sulfasalazine is commonly prescribed for individuals with UC and rheumatologic comorbidities.⁴³ Periodic monitoring of complete blood counts (CBC) and liver function tests (LFT) is recommended.

 

Sulfasalazine may be poorly tolerated due to adverse effects such as headache, nausea, diarrhea, and rash.⁴³ Additional adverse events with sulfasalazine include folate metabolism interference, male infertility, and rare cutaneous side effects such as Stevens-Johnson syndrome. Anemia, leukopenia, or thrombocytopenia are also possible. Pneumonitis and hepatitis have been reported.⁴³  Sulfasalazine is contraindicated if a patient has a sulfa allergy. Sulfasalazine tablets are a yellow/orange color; individuals who take it may notice an orange tinge in urine, tears, and sweat that can stain clothing and contact lenses. Auxiliary labels and counseling should emphasize drinking plenty of fluids, taking the drug on an empty stomach, and avoiding antacids.

 

Mesalamine and Balsalazide

Low dose mesalamine may be prescribed initially at less than 2 grams per day(g/d). Some patients need 2 to 3 g/d. Higher doses of 3 g/d or more may be required to induce remission.³⁶ Combining oral and rectal therapy may deliver a higher effective dose of 5-ASA to the involved area and lead to higher rates of induction and maintenance of remission. This approach may avoid escalation to corticosteroids or other agents.³⁶

 

Mesalamine and balsalazide are associated with rare idiosyncratic worsening of colitis.²² Rare interstitial nephritis may also occur. The prescribing information recommends periodic renal function monitoring. Olsalazine is generally less well tolerated than either mesalamine or balsalazide. Headache, nausea, diarrhea, leukopenia and hepatitis are possible. 5-ASA treatments should be avoided in pregnancy.²²

 

Steroids and Other Traditional Treatments

Corticosteroids, such as budesonide, are generally prescribed for a short duration or for induction of remission.³⁴ Some experts suggest prescribing oral mesalamine, balsalazide or olsalazine over budesonide because hepatic first-pass metabolism lowers budesonide’s systemic activity.^34,44 As the patient’s condition improves, withdrawing the steroids and reaching steroid-free remission (SFR) is important. Long-term corticosteroid use may lead to infection, diabetes mellitus, weight gain, insomnia, osteoporosis, or glaucoma.⁴⁵ Mood changes, cataracts and delayed wound healing are possible.⁴⁵

 

Thiopurines and Cyclosporine

Thiopurines, including azathioprine and 6-mercaptopurine, may improve inflammation in patients with UC. They inhibit the proliferation of lymphocytes and are used to maintain remission. Their dosing is weight-based and their onset of action can be slow, taking up to three months.²² They are often used in combination with biologics. Monitoring for drug interactions is necessary. Allopurinol interactions with thiopurines are especially important because allopurinol inhibits thiopurine metabolism.⁴⁶ The dose of mercaptopurine or azathioprine may need to be reduced to one-third or one-quarter of the normal dose if allopurinol is also prescribed. Prescribers determine dose reductions based on therapeutic response and toxicity.⁴⁷

 

Even though thiopurines and cyclosporine have been prescribed for many years, remaining aware of their side effects is important. Possible adverse events of thiopurines include nausea, vomiting, fever, leukopenia, thrombocytopenia, pancreatitis, and hepatotoxicity. Rare adverse events may include non-Hodgkin lymphoma. Individuals prescribed calcineurin inhibitors, such as cyclosporine, may experience hypertension, nephrotoxicity, hyperkalemia, infection, lymphoma, or diabetes mellitus.³⁷

 

Additional therapies include biologics and newer small molecules (tofacitinib, ozanimod). Before discussing newer therapies, a short review of step-up and step-down approaches is reasonable. If a patient presents with moderate to severe ulcerative colitis, philosophies differ among gastroenterologists regarding beginning with a step-up versus a step-down approach.^36,48

• The step-up approach begins with the traditional therapies mentioned above and followed by biologics and IMM if symptoms persist, if remission is not achieved, and the patient is considered high-risk. Extensive inflammation and the need for repetitive use of corticosteroids are examples of high-risk status.
• The step-down approach occurs when prescribers begin with a more intensive treatment with biologics and IMM and then step down to the medications mentioned above if patients improve.

 

Step Up or Step Down?

A 2021 study (N = 1891) examined UC’s clinical presentation in the five years before starting biologic therapy. The researchers analyzed patients’ experiences, comorbidities, morbidity, and treatment burden over time. Figure 2 summarizes participants’ health burden, disease progression, medication burden, and increased comorbidities. Across the study period, the need for treatment with oral corticosteroids, 5-ASA, and other non-biologic immunomodulators (IMM) increased progressively. Due to the increasing burden, the researchers supported early use of biologics (a step-down approach) rather than gradual step-up after failing conventional therapies for adult patients with moderate to severe UC.³⁰ 

 

Figure 2. Treatment and Health Experience Beginning Five Years Before First Biologic³⁰

5-ASA = 5-aminosalicylates; ED = emergency department; OC = oral corticosteroids; Pts = patients

 

 

Anti-TNF agents

 

Anti-TNF agents are commonly prescribed for moderate to severe UC due to their effectiveness, length of time on the market, and healthcare professional comfort prescribing them.⁴⁴ The U.S. Food and Drug Administration (FDA) has approved many anti-TNFs, but has approved only adalimumab, golimumab, or inFLIXimab for treating UC. Usually, prescribers use anti-TNFs after 5-ASA and corticosteroids in patients with mild to moderate severity and the step-up approach to treatment. Prescribers may prescribe the step-down approach, using biologics earlier, in some cases.³⁸ They often employ concomitant IMM to decrease immunogenicity seen with anti-TNFs.^38,47

 

Because biologics like anti-TNFs are made with living cells, patients may develop an unintended immune response (immunogenicity) in the form of anti-drug antibodies; if they develop, these antibodies may render the anti-TNF medication less effective. The antibodies may bind to the anti-TNF, interfere with its mechanism of action, reduce the anti-TNF’s serum concentration, increase its clearance, and lead to loss of effectiveness. Antibodies may also occur upon restarting an anti-TNF if a patient starts and stops an anti-TNF over time. It is unknown why some people develop anti-drug antibodies and others do not. The presence of antibodies and reduced response often prompt prescribers to switch the anti-TNF to regain effectiveness, and doing so often works. The addition of an IMM can suppress the antibodies which may reduce the risk of switching therapies or avoiding an anti-TNF dose increase.⁴⁷

 

Pharmacy team members should remain diligent about look-alike, and sound-alike names of the anti-TNF agents and should remember that doses of anti-TNF agents vary by indication.

 

SIDEBAR: TECH TALK about Look-alike, Sound-alike medications

Medications with names that look-alike and/or sound alike are classified as high-alert medications.

• Know that inFLIXimab had been confused with riTUXximab, so the Institute for Safe Medication Practices recommends using TALL Man lettering.
• Prevent medication errors between therapies for UC, such as adalimumab and golimumab, ustekinumab and upadacitinib, or vedolizumab and ustekinumab or adalimumab. Segregate the medications in different locations or consider stickers or other alert methods prior to medication dispensing.

 

 

An Anti-integrin

Integrins are adhesion receptors that mediate cell-to-cell and cell-to-extracellular adhesion. Vedolizumab is a humanized monoclonal antibody that binds to the α4β7 integrin, blocks the interaction of α4β7 integrin, and inhibits lymphocyte migration into inflamed GI tissue.⁴⁹ With fewer lymphocytes in the GI tract, vedolizumab helps reduce inflammation and UC symptoms. Vedolizumab can be referred to as a B-anti-integrin and an adhesion molecule inhibitor. Patients with steroid-dependent disease have treatment options, including treatment with thiopurines, anti-TNF agents (may be combined with azathioprine or 6-mercaptopurine), or vedolizumab.³⁸

 

Prescribers and patients may ask about outcomes in clinical trials. A vedolizumab study enrolled patients with an inadequate response or intolerance to IMM therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to an anti-TNF.⁴⁹ Participants received IV vedolizumab 300 mg or placebo at week 0 and week 2. Concomitant stable dosages of 5-ASA, corticosteroids (prednisone dose of 30 mg/day or less or equivalent), and IMM (azathioprine or 6-mercaptopurine) were permitted through week 6. The percentage of patients achieving a clinical response at week 6 was 47%. The researchers also measured remission and found 17% of participants achieved remission at week 6. Those with a clinical response at week 6, or receiving open-label vedolizumab, were invited to enter a 52-week study with every 8-week dosing. At week 52, 42% of participants achieved clinical remission.⁴⁹

 

JAK inhibitors

 

Tofacitinib and upadacitinib are referred to as small molecules because their molecular structure is smaller and simpler than the biologics’, which are large three-dimensional structures. The JAK inhibitors are dosed orally and require a loading dose. JAK inhibitors are indicated for adults with moderately to severely active UC who responded inadequately or couldn’t tolerate one or more anti-TNF agents.³⁹ Many individuals are willing to visit an infusion suite for treatment; however, younger patients and those with very busy lifestyles or heavy travel schedules may prefer the small molecule oral drugs for their convenience.

 

When prescribing JAK inhibitors, pretreatment screening should include assessment for hepatitis B and tuberculosis. When patients start biologics or JAK inhibitors, their immune response may decrease, increasing risk of certain infections, such as hepatitis B or tuberculosis. If patients have active hepatitis B or tuberculosis, they need treatment to eradicate those infections before beginning biologics or JAK inhibitors. A risk of bacterial, viral, and herpes zoster infections exists, so prescribers must assess vaccination status before treatment. CBC and lipid panel monitoring is recommended. Prescribing tofacitinib in combination with biologics for UC or with potent IMM, such as azathioprine and cyclosporine, is not recommended.⁴⁰

 

 

IL-12/23 antagonist

Interleukin 12 (IL-12) and IL-23 are proteins that can cause inflammation. Ustekinumab is a human monoclonal antibody against the shared p40 subunit of IL-12 and IL-23 cytokines. Ustekinumab disrupts inflammation by blocking IL-12/23.⁴¹ The FDA has approved this biologic for adults with various forms of psoriasis, CD, and UC. (It is also approved for children 6 and older for various forms of psoriasis.) In UC in adults, it is typically administered as an IV induction dose, followed by subcutaneous maintenance dosing every eight or 12 weeks. Clinicians should screen for hepatitis B and tuberculosis and monitor CBC every six months.⁴¹ To minimize the risk of medication errors, pharmacy staff should double-check the prescribed route (IV or subcutaneous). They should also be alert for look-alike, sound-alike issues, to prevent prescription transcribing errors or other confusion between ustekinumab and the JAK inhibitor upadacitinib.

 

Research has documented outcomes for this monoclonal antibody, too. A ustekinumab clinical trial assessed efficacy and safety in adults with UC; the primary endpoint was clinical remission at week 8.⁴¹ The researchers randomized participants to a single IV dose of ustekinumab of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo at week 0. Enrollment required previous inadequate response to corticosteroids, IMM, or at least one biologic. At week 8, 19% of participants successfully reached clinical remission.⁴¹

 

S1P Modulator

Ozanimod is an oral sphingosine 1-phosphate receptor (S1P) modulator indicated for the treatment of moderately to severely active UC in adults.⁴² It is also approved for relapsing forms of multiple sclerosis, and the pharmacy team may field questions about this medication’s various indications. Ozanimod binds with high affinity to S1P receptors 1 and 5. It blocks lymphocyte trafficking from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ozanimod may transiently decrease heart rate and cause atrioventricular conduction delays, so a low-dose starter titration pack is available. Prescribers should escalate the dosing slowly to avoid rare but significant bradycardia. Progressive multifocal leukoencephalopathy, a disabling, sometimes deadly adverse event, is rare but possible. Pharmacy teams should counsel patients regarding the need for effective contraception to prevent pregnancy; patients should use contraceptives for three months after discontinuing ozanimod.⁴²

 

An ozanimod clinical trial assessed efficacy and safety using a primary study endpoint of clinical remission at week 10.⁴² It enrolled adults with moderately to severely active UC if they had an inadequate response, or were intolerant, to specific other treatments. The treatments included oral 5-ASA, corticosteroids, IMM (e.g., 6-mercaptopurine and azathioprine), or a biologic (e.g., anti-TNF and/or vedolizumab). The proportion of patients reaching clinical remission at week 10 was 18% with an ozanimod dose of  0.92 mg once daily. Those achieving a clinical response were invited to be re-randomized to a 52-week study extension. The primary endpoint was the proportion of patients in clinical remission at week 52. The proportion of patients with an ozanimod dose of 0.92 mg once daily with clinical remission at week 52 was 37%.⁴²

 

MEDICATIONS IN DEVELOPMENT

Etrasimod is a once-daily, oral S1P receptor modulator in development for the treatment of UC. Results from the phase 2 OASIS trial and open-label extension study revealed patients with moderately to severely active UC who received etrasimod showed improvements in clinical remission and symptom relief beginning as early as week 2. In the phase 3 ELEVATE UC 52 study, 27% of patients in the etrasimod group achieved clinical remission compared with 7% of patients in the placebo group at 12 weeks.⁵⁰ Use of etrasimod in UC is not FDA-approved and regulatory authorities have not yet evaluated its safety and efficacy.

 

Risankizumab-rzaa is an IL-23 inhibitor that is FDA-approved for psoriasis and Crohn’s disease. It is in development for treatment of individuals with UC. In the INSPIRE trial, 20.3% of participants with intolerance or inadequate response to conventional or advanced therapies (biologics, JAK inhibitors, and S1P receptor modulators) achieved clinical remission at week 12.⁵¹ The FDA has not approved risankizumab in UC or evaluated its safety and efficacy.

 

Considerations for Medications in Therapy

Decision-making regarding UC treatment requires consideration of many factors, including

• disease and inflammation location, severity, and extent
• comparative effectiveness and long-term safety of available treatments
• treatment availability
• product labeling
• guideline recommendation
• prior treatment successes or failures
• cost, and
• patient preferences

Since some prescribers may dose escalate to an off-label (higher) dose or off-label shorter dosing interval, pharmacy teams need to remain alert regarding insurance policies that may impact treatment decisions.

 

Safety Information

Each medication’s full prescribing information includes comprehensive safety and efficacy details. The information in this section is not all-inclusive. It’s critical to keep in mind that all UC treatments have limitations. Because most infusions have similar adverse events, Table 5 summarizes select safety information and limitations regarding newer agents used in UC.

 

 

Table 5. Newer Agents: Select Safety Information and Limitations ^{37,41,42,49,52}

Limitations and Safety Considerations	Anti-TNF agents	Anti-IL-12/23 Agents	JAK Inhibitors	Anti-integrin	S1PR modulator
Immuno-suppression	√	√	√	√	√
Infection	√	√	√ (herpes zoster)	√ (upper respiratory)	√
Venous thrombo-embolism			√
Psoriasis	√	√
Major CV adverse event	√		√
Infusion/ injection site reaction	√	√	√	√
Malignancy	√	√	√	√	√
Tuberculosis	√	√	√	√
Worsen CHF	√
Lymphoma	√ (if combine with thiopurines)		√	√
Lymphocyte abnormalities			√
Anemia	√		√
Elevated lipids			√
Headache	√	√	√	√	√
Nausea	√		√	√	√
Fatigue	√	√	√	√	√
Liver function test elevations			√	√	√
Contra-indication if post-MI within 6 months, or unstable angina, stroke or TIA					√
Contraindicated if severe untreated sleep apnea					√
PML				√	√

MI = myocardial infarction; PML = progressive multifocal leukoencephalopathy; TIA = transient ischemic attack

 

Identifying drug interactions is a key skill for pharmacists. Of note, JAK inhibitors can interact with CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) and CYP2C19 inhibitors (e.g., fluconazole, omeprazole).⁴⁰ Drug interactions may be a concern with the use of ozanimod and concurrent IMM, tyramine, antiarrhythmics, beta blockers, or calcium channel blockers.⁴²

 

ACG and AGA Guidelines for the Management of Moderate-to-Severe UC

The American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA) published comprehensive treatment guidelines and interventions for UC.^31,44 Both guidelines cover achieving a response, induction of remission, and maintenance of remission. Select highlights presented below are not all-inclusive.

 

For remission induction, ACG recommends the following options³¹:

• In moderately active UC, oral budesonide MMX
• In moderately to severely active UC, oral corticosteroids
• In moderately to severely active UC, anti-TNF therapy
• When inFLIXimab is used as induction therapy for patients with moderately to severely active UC, it should include a thiopurine
• In moderately to severely active UC, or if failed anti-TNF, vedolizumab
• In moderately to severely active UC, tofacitinib 10 mg orally twice a day for 8 weeks
• For induction of remission in moderately to severely active UC with previous failure of anti-TNF therapy, tofacitinib

 

For maintenance of remission, ACG recommends the following options³¹:

• For previously moderately to severely active UC in remission due to corticosteroid induction, thiopurines
• Continue anti-TNF therapy after anti-TNF induction in patients with previously moderately to severely active UC
• Continue vedolizumab in previously moderately to severely active UC now in remission after vedolizumab induction
• Continue tofacitinib in previously moderately to severely active UC now in remission after induction with tofacitinib

 

The AGA provides the following recommendations for response and remission⁴⁴:

• Current evidence supports use of inFLIXimab, adalimumab, golimumab, vedolizumab, and tofacitinib for remission induction and maintenance in moderate-severe UC
• Thiopurine monotherapy should not be used for induction of remission but may be considered for remission maintenance
• Meta-analysis suggests that inFLIXimab and vedolizumab may be preferred first-line therapy in biologic-naïve patients, rather than standard-dose adalimumab or golimumab
• In patients with prior inFLIXimab exposure, particularly those with primary non-response to induction therapy, vedolizumab or tofacitinib may be preferred over adalimumab or golimumab
• Combination of a biologic agent with an immunomodulator is more effective than monotherapy with either agent
• In patients with moderate-severe disease activity, at high risk of colectomy, biologic agents with or without an IMM, or tofacitinib, should be used early rather than gradual step-up therapy after failure of 5-ASA
• Patients in remission with biologic agents and/or IMM, or tofacitinib, after prior failure of 5-ASA, may discontinue 5-ASA

 

PAUSE AND PONDER: What patient support questions may uncover a patient’s adherence challenges?

 

Patient Education Pearls for Patient Counseling

 

Pharmacy teams have numerous opportunities to provide UC patient education. Because the condition appears differently in affected individuals, conversations should align with the individual patient’s situation. Supportive patient education pearls addressing inflammation and advancing opportunities to remission should be individualized from these topics⁵³:

• UC’s exact cause is unknown
• UC affects people differs widely
• UC is a chronic condition and symptoms wax and wane
• Medications are available to control UC
• The number of people with UC has been increasing
• It can occur at any age and in any racial or ethnic group
• Symptoms will occur in the intestine and may occur outside of the intestine
• Ulcers in the intestine lining that bleed may lead to low red blood cell count (anemia)
• Ask the doctor what tests are needed
• Diet and nutrition plans differ for each patient
• Managing stress is important
• Have supportive friends and family
• Locate restrooms when outside the home
• Carry extra underclothes, toilet paper or moist wipes
• Ask for school or work accommodations

 

SIDEBAR: OTC and Alternative Therapies for Patient Discussion^34,35,44,54

 

Patients with UC may use these OTC products:

• Patients with UC may eat less, thinking it will decrease diarrhea. However, they need proteins, water, vitamins, and minerals to promote healing. Patients need vitamin D and calcium for bones if reduce their dairy intake.
• Bismuth subsalicylate (Pepto Bismol) is an antidiarrheal liquid, chewable tablet, and also swallowable tablet. It helps reduce inflammation in the intestinal lining. Remind patients that it darkens stool and the tongue. That darkening is not a medical concern.
• Simethicone (Gas-X) is an anti-flatulent that helps form gas bubbles in the digestive tract, making them easier to pass and relieving gas pain.
• Loperamide (Imodium) should be taken with caution. It slows digestion. Occasional use may be effective, but patients should consult healthcare providers if they contemplate ongoing use.
• If mild disease persists, such as seen with a Mayo score of 1, the AGA guidelines and some advocacy web sites mention curcumin (a phytochemical from turmeric) or suggest adding curcumin and probiotics for some individuals suffering with UC.
• Patients with severe disease, frequent bleeding, anemia, or abnormal laboratory results may need folic acid. The usual folic acid dose is 1 mg/day. Asparagus, broccoli, and spinach are also foods that contain folate or folic acid.

Patients who have UC should avoid these OTC products:

• Patients should consult their healthcare providers whether to avoid aspirin, nonsteroidal anti-flammatories (ibuprofen, naproxen), lactose, sugar substitutes, or preservatives.
• Patients who take sulfasalazine or mesalamine should not take them with antacids.

 

Many institutions, hospitals and healthcare providers have created UC resources. Table 6 lists  examples of supportive options that can be shared with individuals with UC.

 

Table 6. Patient and Clinician Resources to Support Individuals with UC

Resource	Contact
American College of Gastroenterology	https://gi.org/topics/ulcerative-colitis/ ·       Describes symptoms, tests, diagnosis, risks, surgery and treatments
Cleveland Clinic: Butts and Guts podcast	https://my.clevelandclinic.org/podcasts/butts-and-guts ·       Covers a wide range of gastrointestinal issues including management and surgery ·       Use the search term “ulcerative colitis”
Crohn’s and Colitis Foundation (CCF)	Help Center (referrals, insurance info) https://www.crohnscolitisfoundation.org/ info@crohnscolitisfoundation.org 1-888-MY-GUT-PAIN (888-694-8872- extension 8) Signs and Symptoms https://www.crohnscolitisfoundation.org/sites/default/files/legacy/assets/pdfs/living-with-ulcerative.pdf Spanish Help Center https://www.crohnscolitisfoundation.org/es/home School Accommodation Suggestions https://www.crohnscolitisfoundation.org/justlikeme/living-with-crohns-and-colitis/school/school-accommodations
Mayo Clinic	https://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/symptoms-causes/syc-20353326 ·       Includes a video and written materials on diagnosis, symptom management, and treatment
Downloadable Mobile Apps ·       Download from the App Store or Google Play	My IBD Care: tracks symptoms, flares, medical appointments, BMs, medications Bathroom Scout: Identifies 1.3 million public toilets MyPlate: Monitors calories, the nutrition content of food MyColitis: Health tracking of bowel movements, medications, moods, symptoms, tests

 

CONCLUSION

UC is a debilitating chronic IBD that usually requires long-term treatment to control symptoms and prevent disease-related complications. Many treatments are available; however, the effectiveness, safety, and durability of response and remission vary, and careful assessment of these factors must drive a personalized approach to care. Pharmacy teams must recognize that every patient’s disease is different, and results in diverse manifestations. Pharmacists and pharmacy technicians are ideally positioned to collaborate with multidisciplinary teams to support strategies tailored to each patient to optimize care and to help patients maintain a positive outlook.

 

Many unanswered questions remain about UC. Researchers will continue to evaluate treatment advances and explore disease management opportunities while pharmacy teams encourage patients suffering from UC to have routine doctor visits, adhere to their medication regimen, and maintain a healthy lifestyle.

 

 

 

 

Download CE Activity

 

Introduction and Epidemiology

The American Pet Products Association (APPA) estimates that approximately 70% of Americans keep pets in their household, equating to 90.5 million homes. Dogs and cats are the most popular and live in around 69.0 and 45.3 million U.S. households, respectively, followed by 11.8 million households for freshwater fish, 9.9 million households for birds, and 3.5 million households for horses.¹ Public, residential, leisure, and specific occupational environments (e.g., farms, laboratories, pet shops) have high concentrations of pet allergens because of the high prevalence of community pet-keeping and Americans’ tendency to live indoors. Allergic reactions to pets have been recognized for at least 100 years.² Risk factors for developing asthma and rhinitis include allergies to furry animals, especially cats and dogs.³ Direct or second-hand pet exposure increases the likelihood of exacerbating disease in pet-sensitive people. However, evidence also shows that early childhood exposure to dogs or cats before one year of age may have protective effects in preventing allergic sensitization.⁴

Notably, allergies to unusual or exotic pets have increased over the last decade.⁵ In many urban areas, apartment complexes prevent owning large pets or charge a fee for owning cats and dogs, leading to the choice of smaller, more unusual animals. Some examples of uncommon pets are rodents (mice, rats [which allegedly make very good pets], guinea pigs, and other mammals like ferrets, pigs), amphibians (axolotl [a Mexican salamander], dart frogs, and fire belly newts), and reptiles (snakes).⁶ The allergic signs and symptoms or diseases associated with uncommon pets are like those manifested in cat and dog allergies. In addition, patients may present with respiratory symptoms induced by bird allergens and gastrointestinal symptoms after consuming bird eggs; this is called a bird-egg syndrome.⁷

Overall, the incidence of specific allergy to exotic or uncommon pets is unknown because literature only includes isolated cases or small series. In the United States, an estimated 15% to 30% of people are allergic to their pets.⁸ Among people with pet allergies, a fraction is sensitized to more than one animal. Moreover, according to the Asthma and Allergy Foundation of America, cat allergies are reported twice as often as dog allergies. Animals are also recognized as the third leading cause of allergic asthma, after mites and pollens.⁸ Many people adopt ferrets or rabbits, believing they are hypoallergenic. They are not, and pharmacy staff should be aware of that fact.^9,10 The most frequent allergic reactions result from inhalation, contact, or bites.

This continuing education activity summarizes knowledge of pet allergens, including those from uncommon pets; the allergy reaction mechanism and its signs and symptoms; current advances in diagnosis and treatment methods such as immunotherapy; and recommendations for patient education and counseling.

Pause and Ponder: When patients ask about medication for pet allergies, what kinds of questions should you ask?

PET ALLERGENS

Allergy Mechanisms

Compared with other conditions’ mechanisms, allergy mechanisms are simple and encompass three specific paths: allergic sensitization, allergy, and cross-reactivity.¹¹

• Allergic sensitization is the presence of immunoglobulin E (IgE) antibodies to an allergen.
• Allergy is the occurrence of reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by nonallergic persons and mediated by specific immunologic mechanisms. If no symptoms develop, a person could be sensitizing to a particular allergen but not be allergic.
• Cross-reactivity is the process of IgE antibodies (originally developed against a given allergen) binding to homologous molecules originating from a different allergen source.

Characterizing Pet Allergens

Allergies to pets are common. Pet allergy is an allergic reaction to proteins (allergens) found in animals’ skin cells (dander), saliva, urine, or sweat on their fur.⁵ Allergens within the same protein family can cause cross-reactivity. Most allergens are spread via airborne particles. Dander contains allergens formed in sebaceous gland secretions and saliva. Secretions containing allergens adhere to the hair and stratum corneum of the skin. When an animal sheds, tiny particles disperse into the air and remain buoyant for an extended period of time. After the particles slowly settle onto the floor, furniture, or other items, they can be easily re-dispersed into the air. As a result, pet-sensitive people could experience allergy symptoms in the nose, eyes, and respiratory tract even if the pet is not present.⁵ Additionally, people can carry pet allergens that settled onto their clothing or hair.

For cats and dogs, the primary allergen sources are dander and saliva. Similarly, the primary allergen source in rabbits is saliva. In contrast, the primary allergen source is urine in rodents (e.g., mouse, rat,) and Mustelidae (ferrets and minks).

Rodents are an interesting case study. Most research laboratories experience a very high rate of staff turnover because lab workers develop allergies to rodents. Children who are exposed to rodent urine can develop this allergy, too. Male rodents produce a larger quantity of and more condensed urine than female rodents. This explains why people who commonly come in contact with male rodents are more likely to develop allergic symptoms. Allergy to rodents acts as an occupational hazard for researchers. Mouse urine is the most concentrated of all urines—far more concentrated than any other species.¹² One study showed that 30% of people exposed to mice and 13.7% of people exposed to rats suffered from allergy symptoms.¹² Symptoms range from conjunctivitis to asthma to skin reactions, which makes working with these animals difficult.

Most animal allergens belong to one of three primary protein families. Within the three families, lipocalin-like proteins and the serum albumin family are the two most widely studied. Other identified allergens are considered minor, including gelatins, immunoglobulins, and transferrins presented in secretions and dandruff. Knowledge of these allergens’ allergenicity and cross-activity is essential to improve treatment and prevent allergic reactions. Table 1 summarizes partially characterized pet allergens, including those generated by exotic pets, because not all allergens are fully characterized.⁵

 

Table 1. Summary of Characterized Pet Allergens^13-22

Common Name of Animal	Source	Allergen	Family
Dog	Dander, saliva, hair	Can f 1 (major allergen) Can f 2 Can f 4 Can f 6 Can f 3 Can f 5 Can f 7 Can f 8	Lipocalin Lipocalin Lipocalin Lipocalin Albumin Arginine esterase (kallikrein) Epididymal secretory protein E1 or Niemann Pick type C2 protein Cystatin
Cat	Sebaceous, anal, and salivary gland	Fel d 1 (major allergen) Fel d 2 Fel d 4 Fel d 7 Fel d 3 Fel d 5w Fel d 8 Fed d 6w	Uteroglobin Albumin Lipocalin Von Ebner gland protein Cystatin Cat IgA Latherin-like IgM
Horse	Dander, sublingual, submaxillary salivary glands, and urine	Equ c 1 (major allergen) Equ c 2 Equ c 4 Equ c 3 Equ c 6	Lipocalin Lipocalin Latherin Albumin Lysozyme
Chinchilla	Epithelia, saliva, urine	Chi La Chi Lb	Protein kinase inhibitor Lipocalin
Guinea pig		Cav p 1 (major allergen) Cap p 2 (major allergen) Cap p 3 Cap p 4 Cap p 6	Lipocalin Lipocalin Lipocalin Serum albumin Lipocalin
Gerbil	Epithelial, salvia, urine, sleep bed	Mer un 23kDa Mer un 4	Lipocalin Serum albumin
Siberian hamster	Epithelial, saliva, urine	Phod s 1	Lipocalin
Rat		Rat n 1 (major allergen) Rat n 4 Rat n 7	Lipocalin; alpha-2u-glubulin Serum albumin Immunoglobulin
Mouse		Mus m 1 (major allergen) Mus m 2 Mus m 4 Mus m 7	Lipocalin; urinary prealbumin Unknown Serum albumin Immunoglobulin
Rabbit		Ory c 1 Ory c 2 Ory c 3 Ory c 4	Lipocalin Lipocalin Secretoglobin Lipocalin
Ferret		Mus p 17 Mus p 66	Unknown Serum albumin
Pig	Meat	Sus s 1 Sus s 5 Sus s 6	Serum albumin Lipocalin Serum albumin

Lipocalin Superfamily

More than 50% of allergens identified from furry animals belong to the lipocalin superfamily and are found in animal dander, saliva, and urine.²³ Lipocalins are large proteins and can induce IgE production in a large proportion of atopic individuals (people who have enhanced immune response to common allergens) who are exposed to the allergen source.²⁴

Serum Albumin Family

Serum albumin is a globular protein prone to participation in IgE-mediated cross-reactions.²⁴ Serum albumin is commonly found in pet dander and saliva and causes an allergic reaction by inhalation and ingestion.

Secretoglobin Superfamily

Secretoglobins are the most potent allergens in cats (e.g., Fel d 1) and other pets (e.g., rabbit Ory c 3). Produced by the skin, salivary and lacrimal glands, these proteins have an unknown function. Dried saliva and dandruff are spread as airborne particles and cause sensitization in susceptible people.²⁵

SIGNS AND SYMPTOMS OF PET ALLERGIES

The most frequently observed pet allergies result from inhalation, contact, and bites. The main allergic symptoms are similar across both common and uncommon pet types. They present as rhinitis, conjunctivitis, urticaria (red, itchy welts that result from a skin reaction), and lower and upper respiratory symptoms, which can be mild to severe and rarely cause anaphylactic shock.⁵

Hypoallergenic Pets

“Hypoallergenic” is defined as possessing decreased risk of causing an allergy in people, which means that hypoallergenic animals could still elicit allergies in humans.⁹ To make hypoallergenic animals, breeders or researchers combine breeds that produce less allergen (in dogs, breeders use breeds that shed less than other breeds, or have hair rather than fur). However, animals often have different mechanisms of allergenicity, so infrequent shedding does not solve all allergy problems.

In a dog allergen study, homes that included hypoallergenic dogs had no statistically significant difference in dog allergen levels compared to homes that included non-hypoallergenic dogs. The common allergen in dogs, Can f 1, was reported at similar levels in all groups.²⁵ The frequency of shedding varies in different dog breeds, but all dogs can elicit allergies in humans.

The main allergen in cats, Fel d 1 protein, comes from their saliva and sweat glands. Because of its small size and adhesiveness, Fel d 1 floats around and sticks to everything, making it almost impossible to remove physically. In fact, Fel d 1 measures in at less than one-tenth the size of ribosome; it’s so small, it easily navigates its way deep into the lungs and can precipitate asthma.²⁶ For this reason, making a completely hypoallergenic cat has proven impossible, however vaccines to decrease the production of Fel d 1 protein have been studied; one vaccine is a combination of recombinant Fel d 1, tetanus toxoid protein, and a snippet of the coat of a plant virus.²⁷ Researchers are unsure as to the purpose of Fel d 1 in cats or why levels of Fel d 1 vary.

Ferrets—which are related to otters, minks, weasels—are considered hypoallergenic because they are less likely to cause an allergic reaction compared to other animals. However, they can still provoke allergies in people. Allergies to ferrets come from their hair, saliva, and urine. Ferret hair and saliva is usually easy to control because they shed infrequently and do not lick people like dogs and cats often do. However, urine is harder to control and can cause allergies when owners clean crates.⁹

Rabbits produce allergens through dander, hair from shedding, and saliva. They tend to shed more often than ferrets, around every three months, so keeping up with cleaning may be difficult. Rabbit hair isn’t naturally allergenic, but when rabbits lick their fur, they transfer a saliva protein that is contaminated with the protein allergen.¹⁰

DIAGNOSIS

Skin Prick Test

Allergists (allergy specialists) use skin prick tests together with medical history and physical examinations to rule out or confirm a suspected IgE-mediated animal allergy.²⁸ Manufacturers prepare skin prick tests by extracting natural allergens from animal hair, dander, and urine. The doctor or nurse will prick the patient’s skin on the forearm or upper back and determine if an allergic reaction occurs within 15 minutes. If a patient develops a red, itchy bump where the pet allergen extract is pricked into the skin, the patient is allergic to that pet allergen. Diagnosticians should first use a skin prick test as it is inexpensive, easy to use, and quick to perform. However, allergen concentrations and components are inconsistent, varying among similar commercial tests from different manufacturers. Healthcare providers should be aware that patients’ test results may be inconsistent if they use different skin prick tests at different times.²⁸

Serum-specific IgE Test

Allergists can use a serum-specific IgE (blood) test when patients’ symptoms and skin test results are contradictory or when patients’ skin conditions prevent a skin test. Serum-specific IgE tests can only determine if a patient is sensitized to a specific pet allergen, but it cannot determine if a patient is allergic to that allergen. Serum-specific IgE tests are highly sensitive, but prone to false-positive results. From this perspective, serum-specific IgE tests may be less accurate than skin prick tests.²⁹

Molecular Diagnosis

Recent scientific advances have allowed molecular diagnosis to differentiate patients who are allergic to a single species or sensitized due to cross-reactivity. This method can aid targeted recommendations for avoidance and assess the choice and composition of immunotherapy.²⁸

PET ALLERGY MANAGEMENT

Pet allergies cannot currently be cured. The treatment goal is to control symptoms and improve patients’ functional status and well-being.

Nonpharmacologic Treatment – Avoid & Minimize Allergen Exposure

Current recommendations for managing pet allergy symptoms start with exposure avoidance. Starting when animals are young, bathing them at least once weekly can reduce allergens and eliminate reactions in humans who are exposed to them (see SIDEBAR).³⁰ Immediate removal of animals from the household will not alleviate symptoms if the owner has carpeting and other pieces of furniture/items that the pet slept or sat on. Mammalian allergens are stable and can persist in house dust for up to six months.³² Additionally, using high-efficiency particulate air (HEPA) filters and mattress encasement, vacuuming, and chemically treating carpet are alternative methods for reducing exposure to contaminated materials, but may not reduce disease severity.³³

Pause and Ponder: When patients have pet allergies, which symptoms are best treated with antihistamines?

SIDEBAR: To Bathe or Not to Bathe…^26,31

Bathing a cat or dog regularly appears to reduce the quantity of allergen harbored by the pet. To effectively lower Can f 1 concentrations, owners need to bathe the animal at least twice every week because Can f 1 concentrations rise rapidly, approaching baseline concentrations within three days after washing. Twice-weekly bathing can reduce the amount of recoverable Can f 1 on dogs by more than 80%, but researchers note that ideally, one would bathe the dog two to three times every week. Airborne Can f levels can fall by ruff-ly 40% but will quickly escalate.

However, the beneficial effects of reducing allergen levels by regular bathing are more likely associated with dogs, because their allergen burden returns faster than that of cats. So, bathing animals reduces the amount of allergen far better than vacuuming.

But should companion animals be bathed so often?

Most cats are notoriously averse to bathing, although some breeds like water (i.e., the Bengal). Dogs vary in the response to bathing—some like it, others do not. People who plan to bathe their cats or dogs regularly should do three things:

• Check with a veterinarian or a breed advocacy group. The American Kennel Club indicates that how often an owner should bathe a dog depends on the dog’s coat type and presence or absence of an undercoat (in the latter case, frequent bathing can affect a dog’s temperature regulation). Bathing an animal is not just about a human’s allergies, the animal’s health and welfare should be a primary concern.
• Consider the labor and time involved in bathing a pet often, safely, and well.
• Start when the animal is young.

 

An allergen reducing cat food (Pro Plan LiveClear) is now available, and its manufacturer indicates it reduces the number of allergens in cat hair and dander by 47% after three weeks of feeding.³⁴ It is produced using eggs that contain an anti-Fel d1 antibody. When cats consume the food, the egg powder binds to and neutralizes Fel d1 in the cat’s saliva.³⁴

Pharmacologic Treatment

When avoidance and reducing allergens are not enough, depending on the severity of signs, over the counter (OTC) medications like antihistamines or local/topical steroids may provide temporary relief of allergy symptoms.³⁵ Those symptoms include runny/itchy nose or throat, sneezing, and itchy, red or watery eyes. Combination products that contain both an antihistamine and a decongestant or an analgesic are available but should be used with caution due to the increased risk of adverse effects. Other allergy medications, besides the ones mentioned above, are used less often, including mast cell stabilizers and leukotriene antagonists. Table 2 summarizes common medications (both OTC and prescription) for treating mild to moderate allergy symptoms.³⁵

Table 2. Medications to Treat Allergy Symptoms³⁶

Medication	Mechanism of Action	Adverse Effects	Notes
Antihistamines
1st generation (nonselective, more sedating) * Diphenhydramine, chlorpheniramine, clemastine 2nd generation (less sedating, less drowsiness): Cetirizine,* desloratadine,* fexofenadine,* levocetirizine,* and loratadine* Azelastine has nasal spray* and eye drop formulation. Epinastine and olopatadine* are formulated as eye drops.	Blocks histamine and its binding to receptors, prevents histamine-caused redness, swelling, itching, and changes in secretions during an allergic response	·       Drowsiness ·       Fatigue ·       Headache	The 2nd generation antihistamines are preferred over 1st generation based on safety and efficacy data.
Corticosteroids
Available as tablets, liquids, nasal spray, topical creams for skin allergies, topical eye drops for conjunctivitis.   Some steroids include: beclomethasone, ciclesonide, fluticasone furoate,* mometasone, budesonide,* triamcinolone,* dexamethasone ophthalmic, prednisone, etc.	Anti-inflammatory effect	Short-term use: Weight gain, fluid retention, high blood pressure   Long-term use: Growth suppression, diabetes, cataracts of the eye, osteoporosis, muscle weakness   Side effects of inhaled steroids: Cough, hoarseness, fungal infection of the mouth	Highly effective for allergies but must be taken regularly. It may take 1 to 2 weeks before the full effect.
Decongestants
Available as nasal sprays, eye drops, liquids, and tablets   Some decongestants include: pseudoephedrine,* phenylephrine,* and oxymetazoline* nasal sprays	Shrinks swollen nasal tissues and blood vessels to relieve the symptoms of nasal swelling, congestion, mucus secretion, and redness	·       Increased blood pressure ·       Insomnia ·       Anxiety, feeling nervous, restlessness	Relieve congestion and are often prescribed with antihistamines for allergies   Contraindicated in patients with severe coronary artery disease, severe hypertension, and who concomitantly use monoamine oxidase inhibitors   Short-term use only (~5 days). Long-term use can make symptoms worse.
Combination Allergy Drugs
Some combination drugs include: cetirizine/pseudoephedrine,* fexofenadine/ pseudoephedrine,* diphenhydramine/ pseudoephedrine,* loratadine/pseudoephedrine,* pseudoephedrine/triprolidine* for nasal allergies, and naphazoline/pheniramine* for allergic conjunctivitis	Effects from each component	Side effects from each component	Use with caution due to increased risk of adverse effects
Anticholinergic Nasal Spray
Ipratropium bromide nasal spray to control nasal discharge	Antisecretory properties in the nasal mucosa	·       Bitterness of the mouth ·       Dry nose, nosebleeds, or irritation ·       Dizziness ·       Headache ·       Sore throat ·       Respiratory tract infection	Some patients may feel better right away. For others, it may take 1 to 2 weeks before the medicine helps. It is important for patients to continue use of this medication as instructed.
Mast Cell Stabilizers
Available as eye drops for allergic conjunctivitis and nasal sprays for nasal allergy symptoms   Some mast cell stabilizers include cromolyn sodium,* iodoxamide-tromethamine, nedocromil, pemirolast, etc.	Prevents histamine release from mast cells	Throat irritation, coughing, skin rashes   For eye drops may cause blurred vision, stinging, and burning	For mild to moderate symptoms Not as effective as steroids
Leukotriene Modifiers
Montelukast*: Indicated for adults and pediatric patients six months or older with perennial allergic rhinitis. May be less effective than loratadine or cetirizine for reducing daytime nasal symptoms	Montelukast binds to leukotriene receptors in the human airway (smooth muscle cells and macrophages), preventing airway edema, smooth muscle contraction, and other respiratory inflammation	·       Stomach pain or upset ·       Headache ·       Stuffy nose ·       Cough ·       Fever ·       Rash ·       Irritability	Warn patients to report behavior changes, including suicidal ideation or suicidal behavior Avoid concomitant use of aspirin or NSAIDs in aspirin-sensitive patients
*Indicates over the counter (OTC) medication

 

In general, for conditions eligible for self-care, e.g., allergic rhinitis, patients should start taking OTC allergy medications one week before they expect symptoms from a predictable exposure or as soon as possible before allergen exposure (for episodic exposure).³⁵ Prescribers should tailor the pharmacologic therapy and length of treatment based on symptoms and severity. Usually, complete relief takes two to four weeks. Intranasal steroids control nasal symptoms more effectively than antihistamines, as they inhibit multiple cell types and mediators, and should be recommended for moderate or persistent allergic rhinitis. Decongestants are effective in nasal congestion but have little effect on other symptoms. Intranasal and ocular preparations are available for nasal and eye symptoms. Intranasal cromolyn is the preferred initial choice for pregnant or lactating patients, as the body does not absorb it based on the route of administration. As mentioned in the table, fluticasone and triamcinolone nasal sprays are available over the counter.³⁵

If a patient has persistent allergies, allergy medication is more effective when taken regularly.³⁵ For example, if a patient with moderate or severe persistent allergic rhinitis has completed two to four weeks of treatment with intranasal corticosteroids or oral antihistamine and achieved symptomatic control, healthcare providers can optimize the treatment’s effect by reducing the dose and continuing treatment for one additional month. If a patient’s symptoms are uncontrolled after two to four weeks of OTC treatment, pharmacists should assess the patient’s adherence and refer for prescription therapy if necessary.³⁵

Pause and Ponder: Which providers in your area provide allergen-specific immunotherapy? What should patients expect if they take this route?

Allergy Immunotherapy

Allergen-specific immunotherapy has been used in pet allergies for years and has proven efficacy to help control symptoms and prevent disease progression. Allergists will consider allergy-specific immunotherapy when symptoms are uncontrolled by medications and/or avoidance measures, when adverse drug effects are intolerable, or when patients want to reduce long-term use of allergy medications.³⁷

The basis for allergen-specific immunotherapy is gradual reprogramming of the immune system to build a tolerance to allergens. This class comes in three forms:

• Sublingual allergy immunotherapy (SLIT) tablets
• SLIT drops, and
• subcutaneous allergy immunotherapy (SCIT)

As of 2022, the FDA has approved four SLIT tablets to treat allergic rhinitis with or without allergic conjunctivitis caused by ragweed, northern pasture grasses, and dust mites in susceptible individuals; the FDA has not approved SLIT tablets for pet allergies.²²

SLIT drops are made from FDA-approved allergy extracts used to make SCIT shots. However, these extracts are only FDA-approved for injection use under the skin, and they are not approved for use under the tongue. Therefore, SLIT drops are not FDA-approved and are off-label in the United States, and Medicare or Medicaid does not cover these treatments in most cases. Despite not having FDA approval, patients can still receive SLIT drops from some prescribers who prepare a custom-mixed formulation but must pay out of pocket. Research indicates SLIT is safe and effective.³⁹

The FDA has approved SCIT for cat allergies, but not for other pet allergies. Patients who receive SCIT usually call it “allergy shots.” One systemic review evaluated 88 trials that enrolled 3,459 asthmatic patients and exposed them to SCIT. One case of deterioration in asthma symptoms was avoided for every three patients treated with SCIT (95% CI, 3-5), and one patient would avoid increasing symptomatic medication use for every four patients treated (95% CI, 3-6).⁴⁰ Another study found that SCIT can reduce the need for systemic steroids in allergic rhinitis patients.⁴¹ Usually, the patient receives a solution for injection with 10,000 bioequivalent allergy units (BAUs) per milliliter (standardized extract) of lyophilized cat hair and dander added to glycerol and human serum albumin (0.03%). A clinician administers one to two subcutaneous injections every week starting at low doses (1:10,000 dilution) and titrating up to a seemingly effective maintenance dosing. Then, the prescriber extends the injection interval gradually to every 2 weeks to 4 weeks. For cat allergens, the effective maintenance dose usually falls within the 1000 to 4000 BAU range.⁴²

SCIT sometimes can cause treatment-related systemic allergic reactions; however, near-fatal or severe reactions are rare, and most reactions are local and mild (swelling, pruritis, and redness at injection site).⁴³ SCIT should not be recommended to patients who have severe uncontrolled heart problems or asthma if they take beta-blockers, which are associated with more frequent reactions, more severe reactions, and reactions that are refractory to epinephrine. Additionally, allergy shots should not be recommended for pregnant women unless discussed with their obstetricians.⁴³

Both SCIT and SLIT require gradual up-titration of dosages with ongoing and multiple treatments and may take three to five years to reach desensitization. Also, for SCIT, based on its route of administration (subcutaneous injections are invasive), patients will need to visit the doctor's office more frequently and may experience the treatment-associated side effects.

SLIT has been increasingly recommended because of its ability to modify the immune system for the long term while reducing allergy symptoms. SLIT also showed a safer profile, only associated with mild mouth symptoms, and improved adherence compared to SCIT.⁴⁴ When compared to traditional allergy treatments, SLIT tablets showed similar clinical efficacy to nasal corticosteroids and greater clinical efficacy than second-generation antihistamines and montelukast.⁴⁵

What About Cost?

In adherent patients, SCIT and SLIT have proven to be an economically viable option. The annual cost of using SCIT depends on patients’ insurance: Medicare ($1021.70), Medicaid ($758.16), and the commercial average ($1722.24). Yearly treatment costs for SLIT are self-pay because treatment is not FDA approved and costs around $679.25.⁴⁶ Because SLIT drops are administered at home by patients, they tend to be more affordable than the cost of SCIT. Patient preference might be for a once monthly administration, rather than taking oral antihistamines  daily.

OTC medications are less expensive than immunotherapy, but costs vary. In a comparison of second-generation antihistamines versus montelukast, levocetirizine (Xyzal) had the best efficacy per cost value. Generic fexofenadine (Allegra), although similar in efficacy, was more expensive than levocetirizine.⁴⁴

CONCLUSION

Healthcare providers should counsel patients about reducing allergen exposure and help patients to choose OTC medications for self-care based on individual patient needs and conditions to optimize treatment effects. Pharmacy staff should refer patients to allergists when necessary to identify the cause of their allergy symptoms. If a patient's allergy does not allow him or her to have pets at home and the patient owns a pet, suggest that the patient ask family members or friends about placement before contacting the local animal shelters.

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INTRODUCTION

Asthma and chronic obstructive pulmonary disease (COPD) are common conditions that affect many individuals’ daily functioning. Worldwide, roughly 340 million people have asthma, and 390 million people have COPD.^1,2 It’s well-known that patients often have suboptimal inhaler technique, and numerous professional organizations have advocated for more counseling at every point in the healthcare system.^3,4 Although several new and improved pulmonary inhalation devices are available, inhaler use skills have lagged.⁵

 

Two systematic reviews analyzed studies of inhaler technique among patients and healthcare professionals from 1975 to 2014.^5,6 Each review divided the studies into an earlier (1975 to 1994) and a later (1995 to 2014) period to assess changes over time. The review of 54,354 patients over 144 studies found that approximately 30%, 40%, and 30% percent of patients had correct, acceptable, and poor technique, respectively. There was no significant difference in inhaler use skill between the earlier and later time periods.⁵ The review of 6,304 healthcare professionals over 55 studies found that correct inhaler technique among healthcare professionals declined from around 20.5% in the earlier time period to just 10.8% in the later time period.⁶

 

Using inhalers correctly is essential to disease control. A systematic literature review found an association between inhaler use errors and worsened disease outcomes for patients with asthma and COPD in almost all included studies.⁷ Longitudinal studies found that reductions in inhaler use errors improved disease outcomes.

 

Ultimately, most patients receive their inhalers from a pharmacy. Research shows that community pharmacists can positively impact inhaler technique, asthma control, quality of life, and medication adherence with educational interventions.⁸ Pharmacy personnel are strategically positioned to improve outcomes for people with asthma and COPD by

• Being familiar with the various inhalers available, understanding how to use them, and knowing the counseling points for each
• Recognizing patient-specific factors that could impact inhaler administration
• Understanding the importance of educating and evaluating patients on inhaler technique, and planning how to best deliver this care
  

Medication Classes Found in Inhalers

Several pharmacologic classes of medications (and combinations of these classes) are available in inhaler products:

• Short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) relax airway smooth muscles by stimulating beta_2-adrenergic receptors.⁴ Patients with asthma and/or COPD can use beta agonist medications as needed for relief of acute symptoms, and on a regular schedule for symptom prevention.^3,4
• Short-acting muscarinic antagonists (SAMA) and long-acting muscarinic antagonists (LAMA) cause bronchodilation by inhibiting muscarinic receptors in the airway smooth muscles.⁴ Patients with COPD can use SAMA and LAMA medications as maintenance therapy.^4,9 Patients with asthma who are already using a LABA and an inhaled corticosteroid (ICS) can add on a LAMA maintenance medication if needed.³
• ICS reduce airway inflammation and are used as daily maintenance medications to prevent asthma exacerbations.³ Patients with COPD may also use ICS in combination with LABA or LABA plus LAMA as a daily maintenance medication. Prescribing information for corticosteroid inhalers advises patients to rinse their mouths with water after inhalation and to spit the water out afterward to reduce the risk of fungal infection in the mouth and pharynx.^10-12

 

TYPES OF INHALER DEVICES

 

Pressurized Metered Dose Inhalers

A pressurized metered dose inhaler (pMDI) has two components: a plastic actuator with mouthpiece, and a pressurized canister which may contain^13,14

• the active medication
• a spray-generating propellant to move the medication out of the inhaler
• co-solvents to allow the inhaler ingredients to mix well
• surfactants to stabilize the mixture and prevent drug particles from clumping together or sticking to the canister

The propellant is typically hydrofluoroalkane (HFA), a replacement for the chlorofluorocarbon (CFC) propellants used in many early inhalers.¹³ The Montreal Protocol of 1987 called for phasing out CFCs due to their ozone-depleting properties. The liquid inside a pMDI canister may be formulated as a solution or as a suspended micronized powder. Each time a patient actuates the inhaler (i.e., presses the button to release a spray), a metering chamber in the canister measures the correct liquid volume for that dose. The device releases large particles (about 45 micrometers) from the mouthpiece in a cloud of vapor, and particle size decreases to between 0.5 and 5.5 micrometers as the aerosol evaporates.

 

Pause and ponder: How do you think the ban on chlorofluorocarbons impacted the inhaler market?

 

To maximize lung deposition of medication from a pMDI, patients should take a slow, deep breath lasting about four to six seconds and actuate the inhaler at the start of (or immediately after starting) this breath.¹³ If patients mistime the actuation or inhale too quickly, medication is more likely to deposit on the tongue or the back of the throat and patients will swallow it instead. This phenomenon—also known as oropharyngeal deposition—can reduce the effective medication dose and increase adverse effects (e.g., oral thrush and hoarseness with inhaled corticosteroids).¹³ Table 1 lists the medications available as pressurized metered dose inhalers.

 

Table 1. Pressurized Metered Dose Inhalers^9,10,15-24

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol HFA (Ventolin HFA, ProAir HFA, Proventil HFA, generic)	90 mcg
	levalbuterol HFA (Xopenex HFA, generic)	45 mcg
SAMA	ipratropium HFA (Atrovent)	17 mcg
ICS	ciclesonide HFA (Alvesco)	80 mcg 160 mcg
	fluticasone HFA (Flovent HFA, generic)	44 mcg 110 mcg 220 mcg
	mometasone HFA (Asmanex HFA)	100 mcg 200 mcg
ICS/LABA	fluticasone/salmeterol HFA (Advair HFA)	45 mcg/21 mcg 115 mcg/21 mcg 230 mcg/21 mcg
	budesonide/formoterol HFA (Symbicort, generic)	80 mcg/4.5 mcg 160 mcg/4.5 mcg
	mometasone/formoterol HFA (Dulera)	50 mcg/5 mcg 100 mcg/5 mcg 200 mcg/5 mcg
LAMA/LABA	glycopyrrolate/formoterol HFA (Bevespi Aerosphere)	9 mcg/4.8 mcg
ICS/LAMA/LABA	budesonide/glycopyrrolate/formoterol HFA (Breztri Aerosphere)	160 mcg/9 mcg/4.8 mcg

HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

 

Spacers and Valved Holding Chambers

A spacer is a tube or bag, often made of plastic, that a patient connects to a pMDI before use.²⁵ Medication particles traveling through these devices slow down before reaching the mouth. This also allows the aerosol propellant more time to evaporate, leaving smaller particles to be inhaled. Lower velocity and smaller particle sizes reduce oropharyngeal deposition, so more medication reaches the lungs. However, patients still need to time inhalation with actuation, and they should avoid exhaling into the spacer to prevent dilution (weakening) of the dose.

 

Valved holding chambers (VHC) are like spacers, but they have a one-way valve between the chamber and the mouthpiece.²⁵ VHCs trap the aerosols in the chamber, allowing time for patients with poor hand-breath coordination to inhale their medication. The one-way valve blocks exhalations from reaching the aerosols in the chamber, allowing patients to use multiple inhalations or tidal (restful) breathing if needed. For doses requiring multiple medication puffs, healthcare providers should counsel patients to prepare, actuate, and inhale each puff separately rather than spraying multiple puffs into the spacer or VHC at once.¹³

 

Due to gravity, impaction, and electrostatic charge, some medication is lost in a spacer or VHC before reaching the patient.²⁵ Washing a spacer or VHC with detergent (a water-soluble cleansing agent) and letting it air dry before first use can reduce the electrostatic charge and limit drug particle loss to the device walls. Some spacers and VHCs are made with anti-static material, but often come at a higher cost to the patient.

 

The Global Asthma Network (which aims to improve asthma care, particularly in low- and middle-income countries) advises that people can make effective spacers from 500 ml plastic bottles if commercial spacers are unavailable or too expensive.¹ A cost-effectiveness analysis determined home-made spacers (most of which were made from plastic water bottles) to be more cost-effective than commercial spacers in Columbia (a middle-income country).²⁶ The study found lower overall treatment costs and no difference in hospital admission rates.

 

Breath-Actuated pMDIs

A breath-actuated pMDI of beclomethasone dipropionate HFA (Qvar Redihaler) is available to overcome the problem of hand-breath coordination.²⁷ This inhaler is available in 40 mcg/actuation and 80 mcg/actuation. As the name implies, it actuates when the patient takes a breath, but it does not rely on a high inspiratory flow rate to deliver the medication. An inspiratory flow rate of just 20 L/min activates the inhaler, which then uses the HFA propellant to assist with dose delivery. Other breath-activated inhalers (discussed below) require up to 88 L/min for activation, which may be difficult for individuals with asthma or COPD who are already having trouble breathing. Young children and adults have tidal breathing inspiratory flow rates of 8 to 16 L/min and 13 to 18 L/min respectively.²⁷ Therefore, a breath-activated pMDI may require only a bit more inspiratory effort than the patients’ usual breathing.

 

Soft Mist Inhalers

Soft mist inhalers (SMIs) do not contain a propellant.²⁵ Instead, these inhalers use a spring to create pressure and spray the drug solution through a nozzle, forming two jets of liquid that collide to create a slow-moving mist. The mist’s low velocity increases drug deposition in the lungs rather than the oropharynx. An SMI’s aerosol cloud lasts about six times longer than a pMDI’s, increasing the window for effective inhalation in patients who have trouble coordinating actuation and inhalation. Table 2 shows the medications available as soft mist inhalers.

 

Table 2. Soft Mist Inhalers^28-31

Class	Medication (Trade name)	Dose/actuation
SAMA/SABA	ipratropium bromide/albuterol sulfate (Combivent Respimat)	20 mcg/100 mcg
LAMA	tiotropium (Spiriva Respimat)	1.25 mcg 2.5 mcg
LABA	olodaterol (Striverdi Respimat)	2.5 mcg
LAMA/LABA	tiotropium/olodaterol (Stiolto Respimat)	2.5 mcg/2.5 mcg

LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist; SAMA = short-acting muscarinic antagonist

 

Dry Powder Inhalers

Dry powder inhalers (DPI) are breath-actuated and breath-powered inhaler devices. To improve powder flow and accurate dose metering, manufacturers combine the active medication with a carrier powder or formulate it into spherical agglomerates (small sphere-shaped particles).³² Patients’ inspiratory flow and the resistance inside the inhaler generate turbulent energy that disaggregates (separates) the medication. Quick inhalation optimizes this process. The resulting tiny drug particles (less than 5 micrometers) can reach the lungs, while the larger carrier particles land in oropharynx and are swallowed.

 

DPIs typically require an inspiratory flow rate of at least 30 to 60 L/min, which some patients may have difficulty achieving.²⁵ There is also a possibility of decreased medication delivery from a DPI during disease exacerbations (periods of worsening), when patients’ ability to generate a forceful inspiration may be impaired.³² Table 3 lists available dry powder inhalers.

 

Table 3. Dry Powder Inhalers^15,33-46

Class	Medication (Trade name[s]/generic availability)	Dose/actuation
SABA	albuterol (ProAir RespiClick, ProAir Digihaler)	117 mcg
LABA	salmeterol (Serevent Diskus)	50 mcg
ICS	budesonide (Pulmicort Flexhaler)	90 mcg 180 mcg
	fluticasone propionate (Flovent Diskus)	50 mcg 100 mcg 250 mcg
	fluticasone furoate (ArmonAir Digihaler)	55 mcg 113 mcg 232 mcg
	fluticasone furoate (Arnuity Ellipta)	50 mcg 100 mcg 200 mcg
	mometasone (Asmanex Twisthaler)	110 mcg 220 mcg
ICS/LABA	fluticasone/salmeterol (Advair Diskus, Wixela Inhub, generic)	100 mcg/50 mcg 250 mcg/50 mcg 500 mcg/50 mcg
	fluticasone/salmeterol (AirDuo RespiClick, AirDuo Digihaler, generic)	55 mcg/14 mcg 113 mcg/14 mcg 232 mcg/14 mcg
	fluticasone/vilanterol (Breo Ellipta, generic)	100 mcg/25 mcg 200 mcg/25 mcg
LAMA	aclidinium bromide (Tudorza Pressair)	400 mcg
	tiotropium bromide (Spiriva Handihaler)	18 mcg (per capsule)
	umeclidinium (Incruse Ellipta)	62.5 mcg
LAMA/LABA	umeclidinium/vilanterol (Anoro Ellipta)	62.5 mcg/25 mcg
ICS/LAMA/LABA	fluticasone/umeclidinium/vilanterol (Trelegy Ellipta)	100 mcg/62.5 mcg/25 mcg 200 mcg/62.5 mcg/25 mcg

ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta-agonist

 

INHALER TECHNIQUE EDUCATION

Consider that participants in most randomized controlled trials receive thorough education on inhaler use, must demonstrate competence to be included, and receive ongoing evaluations of their technique.⁴ This is the context in which inhaler efficacy is established. Ideally, all patients would have access to similar standards of care to ensure maximum benefit of inhaled medications. Inhaler technique support can also improve adherence. If patients are using inhalers incorrectly and not seeing clinical improvement, they may discontinue them due to perceived lack of efficacy.⁴⁷ A survey of patients with COPD found significantly greater adherence and confidence in treatment among patients whose inhaler technique had been checked by a healthcare professional within the past two years.⁴⁸

 

Healthcare providers must consider patient preferences, health literacy, and language barriers when choosing appropriate education methods.⁴⁷ A survey of inhaler-using adults seen at a pulmonary clinic or outpatient pharmacy compared education preferences between English and non-English speakers.⁴⁹ Both groups shared a preference for in-person, active learning methods but had low interest in participating in education sessions outside of regular clinic visits. The aforementioned survey of patients with COPD found that 83% thought a demonstration was “very helpful” for learning inhaler technique.⁴⁸ Only 58% and 34% thought the same about a video or leaflet, respectively.

 

Pharmacists Can Improve Inhaler Use

Pharmacists are best placed to provide in-person, active demonstrations to patients where they already come to pick up their medications. Research shows that pharmacists can provide effective inhaler use education (if and when their workflow allows for it). A 2017 systematic review of critical inhaler errors in asthma and COPD found that pharmacist-led inhaler education interventions produced statistically significant improvements in patients’ inhaler technique in seven out of eight studies.⁵⁰

Published studies of pharmacist-led interventions provide examples of counseling methods that have proven effective. A pre- and post-intervention study of 211 patients with COPD in Vietnam examined the efficacy of face-to-face inhaler training with a pharmacist. Training followed this format⁵¹:

• Patients demonstrated technique on a placebo inhaler device
• Pharmacists corrected each mistake and explained why the correction was important
• Pharmacists demonstrated every step verbally and physically with a placebo inhaler
• Patients performed the technique again
• Patients and pharmacists repeated this process until patients could complete all steps correctly

 

This procedure took about six minutes for initial training and three minutes for follow-up trainings.⁵¹ Pharmacists provided training monthly for three months, once at six months, and once at 12 months. They also included label stickers on inhalers with a summary of the steps for use. The percentage of patients using correct inhaler technique increased by over 40% from baseline to six months but declined somewhat between six and 12 months. Researchers concluded that patients benefit from an initial intensive period of repeated training sessions, followed by long-term follow-up at least every three months.⁵¹

 

Another study of 72 subjects examined the efficacy of different inhaler training methods by assigning patients to do one of the following⁵²:

• Read an MDI package insert pamphlet
• Watch a Centers for Disease Control and Prevention video demonstrating technique
• Watch a YouTube video demonstrating technique
• Receive direct instruction from a pharmacist

 

Only two minutes were allotted for the interventions (to mimic what might be feasible in a community pharmacy setting).⁵² The pharmacist-led counseling sessions were loosely scripted based on a checklist of proper inhaler technique. After a pharmacist explained and demonstrated inhaler use, subjects could ask questions if time permitted. Study investigators (including the pharmacists performing the direct instruction sessions) used a standardized checklist to assess all participants immediately following the training. There was a statistically significant difference between pharmacist-led instruction and each of the other interventions but not between any of the three other intervention groups. More than 70% of patients in the pharmacist-led intervention group demonstrated correct inhaler use after training compared with less than 20% of patients in the other intervention groups.⁵²

 

Pause and Ponder: Why might a live demonstration provide better training than a video demonstration of the same time duration?

 

The 2022 GINA report emphasizes the importance of providing patients with ongoing inhaler technique training and assessment. The report recommends that pharmacists, nurses, and other healthcare workers³

• physically demonstrate using placebo inhalers (and spacers or VHCs, if applicable)
• check against a device-specific checklist as patients demonstrate technique
• supply a take-home handout with steps for inhaler use (ideally including pictures)
• check and re-train patients at every opportunity, as errors frequently recur four to six weeks after training

 

Pause and ponder: In your workplace, would it be feasible to provide two minutes of counseling with every inhaler refill? How might you identify patients who most need inhaler use training?

 

Of note, devices exist to evaluate patients’ inspiratory flow and inhalation technique when prescribing, training, or assessing.⁴⁷ Although these may not be feasible to use in most community pharmacy settings (and are outside the scope of this continuing education module), they may be very useful in other settings (e.g., a pulmonary clinic). Devices include the AIM (Aerosol Inhalation Monitor), the In-Check DIAL, and the 2-Tone trainer.⁴⁷

 

Inhaler Administration Counseling

 

pMDIs

Most pMDIs require users to prime (release sprays into the air) before first use (see Table 4).^17-20 When priming a pMDI, users should spray it in the air away from the face. If the inhaler requires shaking, they should also be sure to shake well before each priming spray. Most pMDIs require shaking prior to actuation but some, including Atrovent HFA and Alvesco, do not.^9,10 Patients should always avoid spraying pMDIs into their eyes; the package insert for Atrovent HFA instructs users to close their eyes during inhaler actuation.⁹

 

Table 4. Priming Requirements for pMDIs^10,15-24

Product(s)	Prime before first use and if not used for more than:	Number of Sprays
Advair HFAa	28 days	4 sprays
Proventil HFA Ventolin HFAb	14 days
Bevespi Aerosphereb Breztri Aerosphereb Flovent HFAa	7 days
Asmanex HFA Dulera	5 days
Xopenex HFA	3 days
ProAir HFAb	14 days	3 sprays
Alvesco	10 days
Symbicorta	7 days	2 sprays
Atrovent HFA	3 days

^aAlso need to be primed if dropped; ^bAlso need to be primed after cleaning; HFA = hydrofluoroalkane

 

The following are general administration instructions for pMDIs^17-20:

1. Check for a firm fit of the canister in the actuator
2. Remove cap from mouthpiece and check mouthpiece for any foreign objects
3. If product requires shaking, shake well (typically for 5 seconds)
4. Facing away from the inhaler, exhale completely
5. Holding inhaler upright with mouthpiece down, place mouthpiece in mouth
6. Form a tight seal with lips, keep tongue below mouthpiece, and tilt head back slightly
7. While breathing in deeply and slowly through the mouth, press down on the canister until it stops moving and has released a puff and remove finger from the canister
8. Continue to breathe in as long as possible, then remove the mouthpiece
9. Hold breath as long as is comfortable (up to 10 seconds)
10. Breathe out gently, away from the inhaler
11. Replace cap right away

Patients should never use the canister of one inhaler with the actuator of another inhaler.^9,23,24 Patients should clean pMDIs at least once a week. Cleaning instructions for pMDIs vary by product (see Table 5).

Table 5. pMDI Cleaning Requirements^10,15-24

Product	Cleaning instructions
Proventil HFA	Remove the canister from the actuator; DO NOT let the canister get wet. Remove the cap from the mouthpiece. Run warm water through the top and bottom of actuator for 30 seconds in each direction. Thoroughly shake dry. Check the mouthpiece for remaining medication buildup. Let air-dry completely (overnight if possible).   If not fully air-dried before next dose, shake the plastic actuator as dry as possible, insert the canister, shake the inhaler, and actuate it twice. Repeat the original cleaning procedure after taking the necessary dose(s).
Ventolin HFA
Xopenex HFA
ProAir HFA
Atrovent HFA
Bevespi Aerosphere
Breztri Aerosphere
Flovent HFA	Clean after evening dose. DO NOT remove the canister from the actuator. Use a water-dampened cotton swab to clean the small circular opening where medicine sprays out of the canister, twisting in a circular motion. Repeat with a new damp swab. Wipe the inside of the mouthpiece with a clean, damp tissue. Let air dry overnight.
Advair HFA
Asmanex HFA	DO NOT remove the canister from the actuator. Wipe inside and outside surfaces of the actuator with a dry, lint-free tissue or cloth. DO NOT wash or put any parts in water.   Use a dry folded tissue to wipe over the front of the small hole where the medicine comes out of the Alvesco inhaler.
Alvesco
Symbicort
Dulera

HFA = hydrofluoroalkane

 

All available MDI inhalers have dose counters built into either the canister or the actuator. For most products, the dose counter’s numbers or background will change to red when the inhaler is running low, reminding patients to refill their medication. Healthcare providers should counsel patients not to use inhalers after the dose counter reads zero, even if the canister does not feel empty and still operates. People should not put canisters in water to see if they float as a means of gauging whether medication remains (an old trick that is no longer recommended) or try to alter dose counters. They should also never use a sharp object to unblock an actuator or throw a pMDI into a fire or incinerator. All pMDI inhalers require storage at room temperature, and most should be stored with the mouthpiece down so that the tip of the canister valve is facing down. This keeps the gasket inside of the canister wet so that it does not become brittle and allow outside moisture to enter the canister.⁵³

 

In addition to general counseling for pMDIs, specific counseling points for breath-actuated pMDIs include four points⁵⁴:

• There is no button to press; opening the cap prepares the dose. If patients leave the cap open for more than two minutes, they will need to close and reopen the cap before inhaling their dose.
• Do not shake (especially not with the cap open, as this may actuate the inhaler). Do not prime or use with a spacer or VHC.
• Clean weekly with a clean, dry tissue or cloth
• Do not take the inhaler apart

 

SMIs

To set up an SMI (Respimat inhaler), remove the clear base, label the cartridge with the discard date (three months from first use), and insert the narrow end of the cartridge into the inhaler.^28-31 With the inhaler on a firm surface, push down until the cartridge clicks into place (this often takes more force than patients expect). Replace the clear base so that it clicks into place. Do not take the inhaler apart after assembly. To actuate the inhaler, patients should remember the acronym TOP:

• Turn the clear base half a turn in the direction of the arrows until it clicks
• Open the cap fully
• Press the dose-release button and close the cap.

Before first use, repeat the actuation steps until a mist is visible. ^28-31 Then repeat three more times. To take an inhalation

 

1. Turn the base and open the top
2. Fully exhale away from the inhaler
3. Put mouthpiece in mouth and form a tight seal with lips, keeping mouthpiece above the tongue and pointing towards the back of the throat; be sure not to block air vents with lips or fingers
4. While taking a slow, deep breath through the mouth, press the dose-release button and breathe in as long as possible
5. Remove inhaler from mouth and hold breath as long as is comfortable (up to 10 seconds)
6. Breathe out slowly away from the inhaler
7. Close cap

Pharmacists should counsel patients to prime the device with one puff if not used for more than three days or four visible puffs if not used for more than 21 days. ^28-31 Patients should clean the SMI’s mouthpiece (including the metal part inside) once a week with a damp cloth or tissue. These inhalers have dose indicators and automatically lock when empty. Patients should not spray the device into their eyes or use the SMI with a spacer or VHC. SMIs require room temperature storage.

 

DPIs

To administer DPIs^33-36

1. Open cover or remove cap and check mouthpiece for foreign objects

1. Prepare dose (see Table 6)
2. Fully exhale away from the inhaler
3. Put mouthpiece in mouth and form a tight seal with lips, keeping tongue below mouthpiece; be sure not to block air vents with lips or fingers
4. Breathe in quickly and deeply, generating a forceful breath right from the start of inhalation
5. After breathing in all the way, remove inhaler from mouth and hold breath for as long as is comfortable (up to 10 seconds)
6. Breathe out slowly away from the inhaler
7. Cover mouthpiece

 

Table 6. Preparing and Administering DPI Doses^{15,33-37,39-46}

DPI Type	Dose Preparation and Related Notes
Digihaler	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Built in sensors track adherence and inspiratory flow rates. The inhaler sends information to an application using Bluetooth technology. The inhalers work even if they are not wirelessly connected to the mobile application.
Diskus	Hold inhaler in left hand with thumb of right hand in thumb grip. Push thumb grip away to snap mouthpiece into place. Hold in a level, flat, horizontal position. Slide lever away from mouthpiece until it clicks. Keep holding Diskus level during inhalation. To close after inhalation, patients put their thumb in the thumb grip and pull back towards themselves until the inhaler clicks shut over the mouthpiece. Do not close before inhaling, tilt, play with the lever, or move the lever more than once; doses may be lost.
Ellipta	Open the cover until it clicks. If patients open and close the cover without inhaling the medicine, the dose will be lost inside the inhaler, but patients will not receive a double dose.
Flexhaler	Hold brown grip in one hand and use the other to twist off white cover. Hold inhaler upright with one hand still on brown grip and the other in the middle of the inhaler. Twist brown grip as far as possible in one direction, and then back all the way in the other direction. Priming is required before first use (follow instructions for preparing a dose twice). The inhaler will click in the process of preparing a dose. Do not click the brown grip multiple times without inhaling. The dose indicator will count down with each click. However, it is not possible to receive more than one dose at a time. Do not shake the inhaler after preparing a dose.
Handihaler	Press green button and pull cap away to uncover mouthpiece. Then pull mouthpiece away to uncover center chamber. Remove a capsule from blister packaging (without using sharp instruments) and place it in the center chamber. (Discard unused capsules accidentally exposed to air. Close mouthpiece until it clicks. With mouthpiece pointing up, press green piercing button until flat against base only once, then release. Do not shake. When the capsule is pierced, small pieces of gelatin may be created. These may end up in the mouth or throat and are not harmful. Hold inhaler horizontally when inhaling and inhale twice from the same capsule. The capsule should rattle during inhalation. Do not swallow or manually open capsules.
Pressair	Hold inhaler horizontally with green button on top. Press and release the green button to prepare dose. Do not tilt inhaler. Check that control window changes to green. Do not hold green button down when inhaling. Correct inhalation causes an audible click and control window changes from green to red. Pushing green button multiple times before inhaling does nothing; patients will not lose a dose or get a double dose.
RespiClick	Holding inhaler upright, open cap fully until it clicks (the click can be felt and heard). Always close the cap after each inhalation. Patients will waste the medication if they open and close the cap without inhaling.

 

 

Patients may or may not taste or feel the powder from a DPI upon inhalation. It is fine if they do, and they should not take an extra dose if they don’t. Patients cannot use spacers, VHCs, or masks with DPIs. Manufacturers formulate most DPIs with lactose powder as an ingredient, so patients with severe milk protein allergies should not use them.

 

Individuals should not wash DPIs. If cleaning is necessary, using a dry tissue or cloth is appropriate. Patients should store DPIs at room temperature and protect them from heat and humidity; they are more sensitive to humidity than are other inhalers. They should not store the Tudorza Pressair inhaler on a vibrating surface.

 

DEVICE SELECTION TO MATCH PATIENT NEEDS

Individualizing delivery device selection is crucial for optimizing outcomes of aerosol drug therapy. Healthcare professionals must consider patient-, drug-, device-, and environmental-related factors. A good starting point may be to observe a patient’s natural inhalation.⁵⁵ For example, if the patient instinctively takes slow, deep breaths, a pMDI or SMI might be a good fit. If the patient tends to inhale quickly and deeply, a DPI may be ideal. Table 7 discusses other important factors to consider.

 

Table 7. Inhaler Suggestions Based on Patient-Specific Factors^25,27,56-58

For people with…	…Consider
Inability to achieve a good lip seal around an inhaler’s mouthpiece (e.g., pediatric, facial weakness, cognitive impairment)	pMDI with spacer/VHC and facemask
Inability to learn and perform specific breathing techniques	pMDI with VHC
Difficulty generating an inspiratory flow rate of at least 30 to 60 L/min (e.g., older age, female gender, airflow limitation, respiratory muscle weakness, lung hyperinflation, history of COPD exacerbations requiring hospitalization)	pMDI; breath-actuated pMDI; SMI
Poor manual dexterity or limited hand strength	Breath-actuated pMDI; SMI (may need help with initial cartridge installation); DPI (one that does not require complicated manipulations for dose preparation)
Difficulty with hand-breath coordination	Breath-actuated pMDI; pMDI with VHC; DPI; SMI
Inability to store inhaler away from heat and humidity	Non-DPI inhaler (particularly sensitive to heat and humidity)

COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; pMDI = pressurized metered dose inhaler; SMI = soft mist inhaler; VHC = valved holding chamber

 

Patients often use multiple inhaled medications for asthma and COPD. Prescribing the same inhaler type for all a patient’s inhaled medications eliminates confusion over varying administration techniques.⁵⁹ Clinicians can also prescribe combination products where appropriate to simplify treatment regimens.

 

Consider the Cost

Affordability is another vital consideration and will depend on the patient’s insurance status. While most inhalers are brand-name only, a few generic inhalers are available (see examples in Tables 1-3). Prioritizing patient preference when selecting inhalers can improve adherence.⁶⁰ Central to patient satisfaction are issues such as simplicity of use, treatment time, comfort, portability, cleaning requirements, taste, and effect on the throat. If a patient remains unable to use a device effectively after several training visits, consider switching to another inhaler type.

 

INHALER USE MISTAKES

A literature review and meta-analysis of inhaler use errors in patients with asthma and COPD found that 50% to 100% of patients made at least one error when using their inhaler. Error rates were higher for patients⁶¹

• using MDIs compared to those using DPIs
• with COPD compared to those with asthma
• with a longer history of device use compared to patients new to inhaler treatment
• using multiple inhalers compared to those using only one inhaler

 

Errors are also common in patients using SMIs. A systematic literature review and meta-analysis of patients with COPD, bronchitis, or emphysema found that nearly 60% made at least one error when using a SMI.⁶² Other factors associated with higher error rates include^50,61

• older age
• lower education level
• female gender
• lower socioeconomic status
• having two or more comorbidities

 

Pause and ponder: In your workplace, would it be feasible to provide training and technique assessment with every inhaler refill? If not, how might you identify and prioritize patients who most need inhaler use training?

 

While perfect inhaler use is ideal, patients often have complex medication regimens and healthcare professionals often have heavy workloads. It’s vital to prioritize the most essential steps in the inhaler use process, including those that have a proven impact on patient outcomes. The CRITIKAL study used data from the iHARP asthma review service (a multicenter cross-sectional study of adults with asthma) to identify inhaler use errors associated with worsening asthma control.⁶³ Investigators used data from 3660 patients to pinpoint these critical errors which included⁶³

• not opening the cover or removing cap from mouthpiece
• insufficient inspiratory effort
• incorrect position of head
• not breathing out before inhalation
• not holding breath after inhaling medication, or holding for less than three seconds
• not sealing lips around mouthpiece
• incorrectly priming, timing, or inhaling the second dose (if needed)

 

Demonstration Devices

Demonstration devices are placebo inhalers, meaning they contain no active medication. They may be available free of charge from device manufacturers. These are ideal for training since the lack of active drug allows for repeated cycles of education and patient demonstration (“teach-back”). Many demonstration inhalers are specifically marked as “only for use by a single patient” to prevent the possible spread of disease.⁶⁴ Keep demonstration inhalers in a separate area of the pharmacy, and do not send them home with patients to avoid any confusion.⁶⁵

 

We collected the following information by calling inhaler manufacturers directly. Typically, anyone in a healthcare provider’s office or pharmacy is allowed to order demonstration devices on behalf of a prescriber or pharmacy. To order demonstration devices

1. Determine the patient population and disease state you will be addressing
2. Generate a list of common devices your patients use
3. Identify the manufacturer of each device and visit the manufacturer’s website or the website for the specific product
4. Obtain the email and phone number for customer service representatives and note days and times available (keep in mind the time zone)
5. Reach out to the company’s local representative or customer care representative to request demonstration devices
6. Provide all information required (generally your full name, title, state license number, phone number, address of the pharmacy or office you plan to have the devices delivered to and the facility’s secondary contact information [e.g., fax, email])

 

When making a demonstration device request, pharmacy staff should allow several weeks for processing and device delivery. The number of devices available also varies. For example, one inhaler manufacturer provides 15 or 20 demonstration devices in response to requests, while another requires a manager review of any request for more than three devices.

 

Appendix 1 provides contact information for the manufacturers of several inhaler devices. Demonstration device availability can change over time; some companies have demonstration devices in stock only periodically and will advise calling back another time. Companies may also stop carrying demonstration devices for their older products. The GOLD report identifies a lack of placebo inhalers as a common barrier to educating patients.⁴ However, if efforts to obtain demonstration devices are unsuccessful, pharmacists can teach patients using their own devices instead.

 

Manufacturers may also provide patient assistance programs and co-pay assistance to help with affordability. Patients with commercial or private health insurance are often eligible to participate in co-pay assistance programs and receive a savings card to help lower the cost of the prescription. Healthcare providers can also request additional educational materials and pamphlets to hand out. Referring patients who may be struggling with affording their medications to the manufacturer for assistance and to investigate the patients’ benefits to determine discounts available is highly recommended.

 

CONCLUSION

Pharmacy personnel are well positioned to help patients maximize the benefit of their inhaled medications. An awareness of available inhalers and the requirements and techniques for their use can help healthcare professionals identify whether patients and their devices are a good match. Recognizing the importance of ongoing training and assessment, pharmacy staff can encourage brief yet frequent counseling sessions with patients as they refill their inhaled medications. Pharmacy personnel should proactively order inhaler demonstration devices from manufacturers (if available) to facilitate patient education.

 

 

Good	Better	Best
1. Be familiar with different inhaler devices, including counseling points and potential barriers to use for each 2. Encourage any patient picking up an inhaler to speak with the pharmacist about technique 3. Provide pictorial instructions for use with every inhaler	1. Obtain inhaler demonstration devices and use them with patients 2. Based on refill patterns, recognize patients who may be over- or under- using inhalers and assess for suboptimal technique 3. Check against a device-specific checklist when assessing patient technique	1. Check and re-train on inhaler technique at every opportunity 2. Explain the reason behind any corrections 3. Repeat the teach-back/correction cycle until patients are confident and competent

 

 

 

Appendix I. Inhaler Manufacturer Contact List (Current as of July 1, 2022)

Company	Products (demo device unavailable)	Business Contact
AstraZeneca	Symbicort HFA Pulmicort Flexhaler Bevespi Aerosphere Breztri Aerosphere	1-800-236-9933 Monday-Friday, 8am-6pm ET   https://www.astrazeneca-us.com/az-in-us/Contact-us.html   Discount card eligibility: https://www.azandmeapp.com/home.html
Boehringer Ingelheim Pharmaceuticals, Inc.	Spiriva Respimat Striverdi Respimat Combivent Respimat Stiolto Respimat Atrovent HFA Spiriva Handihaler	Direct Representative Line: 1-800-243-0127   https://www.boehringer-ingelheim.us/contact-form   Patient assistance program: 1-800-556-8317 or www.bipatientassistance.com
GlaxoSmithKline (GSK)	Breo Ellipta        Ventolin HFA Trelegy Ellipta   Flovent HFA Anoro Ellipta      Advair HFA Incruse Ellipta    Flovent Diskus Arnuity Ellipta   Serevent Diskus                              Advair Diskus	GSK Response Team: 1-888-825-5249 Monday-Friday, 8:30am-5:30pm ET   https://www.contactus.gsk.com/callback/hcp.html   Discount card eligibility: www.gskforyou.com
Organon & Co.	Asmanex HFA Dulera HFA Asmanex Twisthaler	Service Center: 1-844-674-3200   Coupons for patients with private insurance: www.asmanex.com ; www.dulera.com
Mylan	Wixela Inhub	Customer Relations Team: 1-800-796-9526   Discount card eligibility: www.wixela.com
Sunovion	Xopenex HFA	Customer Service (Respiratory): 1-844-276-8262
Teva	albuterol sulfate HFA (generic) ProAir RespiClick levalbuterol tartrate HFA (generic) fluticasone propionate/salmeterol inhalation powder, USP QVAR Redihaler	Clinician Support Line: 1-877-867-3034   Patient assistance program: 1-800-896-5855

HFA = hydrofluoroalkane

All information was obtained by calling companies directly and was up to date as of July 1, 2022.

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INTRODUCTION

The medical community’s understanding of Sjogren’s syndrome (SjS) has evolved a great deal since it was first recognized in the late 1800s. A surgeon reported the first clinical case of what is now called SjS in 1888, describing a male patient with painless bilateral swelling of the lacrimal, parotid, and submandibular glands (i.e., the glands that produce tears and saliva).¹ Following a series of case reports over about a century detailing a “dry eye-dry mouth-arthritis” illness, physicians pieced together and named the syndrome known today as SjS.^1,2

 

Epidemiologic data about SjS in the United States (U.S.) is limited. It is estimated to affect about 2 to 4 million Americans, but only about 1 million are definitively diagnosed.^3,4 Women are nine times more likely to have the condition, and it typically emerges around menopause (i.e., after age 50). SjS is the second most common rheumatologic disorder in the U.S. behind systemic lupus erythematous (SLE).⁵ Autoimmune conditions don’t discriminate; many famous people have historically battled them publicly. Selena Gomez postponed a concert tour to undergo treatment for SLE. Kim Kardashian suffers from psoriasis. SjS, as a rarer condition, doesn’t make the news quite as often as other autoimmune conditions, but here are a few people you may recognize who are battling the disease today^6-8:

• Carrie Ann Inaba: In 2021, the 30-season judge of Dancing with the Stars and co-host of The Talk took a leave of absence from television to focus on her health and wellbeing. The chronic pain associated with her SjS, SLE, fibromyalgia, and rheumatoid arthritis forced her to stay in bed three days a week.
• Shannon Boxx: This World Cup soccer player and Olympic gold medalist was diagnosed with SjS in 2002 and suffered from severe fatigue and joint pain. Ahead of the 2007 World Cup, she was put on corticosteroids to alleviate her symptoms and needed specific approval from the U.S. Anti-Doping Agency to take them while competing.
• Venus Williams: While dominating the sport of tennis as the most decorated female tennis player to compete in the Olympic Games, she has also been in a battle against her own body. SjS-related fatigue caused her to pull out of the 2011 U.S. Open, and she was temporarily booted from the top 100 tennis players for the first time in 15 years.

 

As an autoimmune condition, SjS’s cause is unclear. Genetic, environmental, and hormonal factors likely work collaboratively to produce the cardinal symptoms of dry eyes and/or mouth, fatigue, and limb pain. Some patients experience additional manifestations in the lymph nodes, lungs, kidneys, muscles, nervous system, skin, teeth, and brain. Glandular and joint involvement is also possible, and constitutional symptoms (e.g., fever, involuntary weight loss, night sweats) can affect quality of life. Patients with SjS have an elevated risk of lymphoma, about 15 to 20 times higher than the general population.^9,10

PAUSE AND PONDER:  Why are patients with SjS so difficult to identify and diagnose?

Clinical Presentation

SjS is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Since it impacts multiple systems in the body, SjS can manifest in various ways. Affected patients may have symptoms that cycle between mild and severe. Symptoms also tend to worsen as patients age and the function of the exocrine glands subsides.

 

SjS’s main symptoms are dry mouth and dry eyes (collectively, sicca). More than 95% of patients with SjS present with sicca symptoms, which are irritating and poorly tolerated.¹¹ About half of patients also have dermatologic involvement (i.e., dry skin or rashes).^3,12 Xerostomia (oral dryness) can substantially impact daily life, interfering with eating, speaking, or sleeping.⁴ When patients’ salivary volume decreases, they also lose saliva’s antibacterial properties. This can accelerate tooth decay, infection, and periodontal disease. Patients with dry mouth also report swallowing difficulties, halitosis (bad breath), and burning sensations in the mouth. Using artificial saliva products to manage dry mouth is time-consuming and ineffective for many patients with SjS.¹³

 

Patients with ocular dryness complain of itchy, gritty, sore, or dry sensations in the eyes despite appearing physically normal.⁴ Decreased tear production over time can cause chronic irritation and destruction of conjunctival epithelium that lines the inside of the eyelids and covers the sclera (whites of the eyes).

 

Patients may also experience symptoms elsewhere in the body, including

• Dry cough
• Fatigue
• Joint and muscle pain
• Numbness or tingling of the hands and feet
• Vaginal dryness

 

Patients who develop musculoskeletal symptoms may have difficulty remaining active. About 53% of patients experience arthralgias (joint stiffness) and 22% experience myalgias (muscle pain).⁴ SjS-associated arthralgia occurs primarily in small joints, sometimes asymmetrically. Providers may confuse these symptoms with SLE or rheumatoid arthritis.

 

Disease Classification and Severity

Experts classify SjS as primary or secondary (see Table 1). Primary SjS (pSjS) is an autoimmune disease that causes immune cells to mistakenly attack and destroy healthy cells in the glands that produce tears and saliva. SjS can also be secondary to other autoimmune diseases (e.g., SLE, rheumatoid arthritis, scleroderma), as is the case for about 60% of patients.⁴

Table 1. American-European Consensus Group Criteria for the Classification of SjS¹⁴

Primary SjS Criteria	Secondary SjS Criteria	SjS Exclusion Criteria
At least 4 of the following, including at least criterion 5 or 6: 1.   Ocular symptoms (dry eyes for ≥ 3 months, foreign-body sensation, use of tear substitutes > 3 times daily) 2.   Oral symptoms (dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing) 3.   Ocular signs (Schirmer test* performed without anesthesia [< 5 mm in 5 minutes], positive vital dye staining results) 4.   Oral signs (abnormal imaging of salivary glands, unstimulated salivary flow < 1.5 mL in 15 minutes) 5.   Positive minor salivary gland biopsy findings 6.   Positive anti-SSA or anti-SSB antibody results	In the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5 for primary SjS.	Any of the following: ·     AIDS ·     Graft versus host disease ·     Hepatitis C virus infection ·     Past head-and-neck radiation ·     Prior lymphoma ·     Sarcoidosis ·     Use of anticholinergic drugs

*Schirmer test is used to determine whether the eye produces enough tears to keep it moist; AIDS = acquired immunodeficiency syndrome; SjS = Sjogren’s syndrome; SSA = Sjogren's syndrome A; SSB = Sjogren’s syndrome B

 

There is a broad range of disease severity in SjS. Some patients experience mild glandular dryness and constitutional symptoms while others have severe glandular involvement and various manifestations throughout the rest of the body, including systemic autoimmune features. Mild SjS has a good prognosis, but patients often have difficulty managing their symptoms and moderate-to-severe disease can severely impact quality of life.¹⁵ SjS symptoms cause considerable psychological distress. About one third of patients with the condition have clinically significant anxiety and half have diagnosable depression.¹⁶

 

Measuring Systemic Disease Activity

The European League Against Rheumatism (EULAR) created a disease activity index for primary SjS (ESSDAI) to measure systemic disease activity.^17,18 The ESSDAI includes 12 domains: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathic, and biological. Each domain is divided into three or four levels of activity, and patients are scored based on that domain’s severity (i.e., 0 indicates no activity and 3 or 4 indicates high activity).¹⁸

 

Each domain’s weight reflects its relative importance to disease activity, and the score for each domain is equal to the level of activity multiplied by the domain’s weight. A final ESSDAI score (i.e., the sum of all the domain scores) could theoretically be between 0 and 123. Patients’ disease activity based on ESSDAI score is as follows^17,18:

• 0 = no activity
• 1 to 4 = low activity
• 5 to 13 = moderate activity
• 14 or greater, or high activity in any domain with a definition of high activity = severe activity

 

Measuring Patient-Reported Outcomes

EULAR also created the SjS patient reported index (ESSPRI) to assess patient-reported outcomes in pSjS.¹⁸ This scale focuses solely on the three major manifestations of SjS: dryness, fatigue, and musculoskeletal pain. Patients rank each of these domains on a scale of 0 to 10, and the total ESSPRI score is the mean (average) of those scores. A “patient acceptable symptom state” is defined as an ESSPRI score of less than 5, and clinicians and researchers define “minimally clinically important improvement” as an increase in ESSPRI score 1 point or more or 15%.¹⁸

PAUSE AND PONDER:  How would your daily life change if you had SjS? What hardships might you face?

Recognition and Treatment are Inadequate

SjS’s variable symptoms are not always present at the same time, leading providers—including physicians, dentists, and ophthalmologists—to treat each symptom individually, unaware of the systemic disease’s presence. Patients suffer from SjS symptoms an average of 10 years before obtaining a diagnosis.^4,19 The condition has historically been misdiagnosed because providers consider symptoms minor or vague and they often mimic other diseases. Up to 30% of people 65 years or older, with SjS or not, report dryness of the eyes and mouth.¹⁹ Sicca and/or parotid gland enlargement can result from various other conditions, including¹⁹

• Alzheimer’s disease
• anxiety and depression
• Bell’s palsy
• bulimia
• chronic conjunctivitis or blepharitis (inflammation of the membrane on the eye or the eyelid, respectively)
• chronic pancreatitis
• complications from contact lenses
• dehydration
• diabetes mellitus
• hepatitis C
• Parkinson’s disease
• rosacea
• viral infections (e.g., cytomegalovirus, influenza, mumps)

 

About half of patients with SjS lack a definitive diagnosis, so undertreatment is considerable.⁴ For those who are diagnosed, treatment guidelines have historically been unclear and available treatments are limited and often unsuccessful. Recently, evidence-based treatment guidelines have emerged (discussed below) to help providers make decisions regarding SjS care. SjS is incurable; targeted, disease-modifying therapies are needed.

 

DISEASE MECHANISMS AND BIOMARKERS

pSjS’s pathogenesis is complex and multifactorial. Underlying genetic predisposition, epigenetic mechanisms (i.e., things that cause changes that affect the way your genes work), and environmental factors contribute to disease development.²⁰ There is no identified causal agent for SjS and it presents with multiple organ involvement. This makes the pursuit for defining an etiology and identifying biomarkers all the more important.

 

Researchers historically considered SjS a specific, self-perpetuating immune-mediated loss of exocrine tissue as the main cause of glandular dysfunction.²⁰ Today, with more sophisticated research methods, experts believe this fails to fully explain several SjS-related phenomena and experimental findings.

 

Genetics and Epigenetics

Genetic studies are a powerful tool for discovering new pathogenic pathways. Scientists have made great strides in studying genetic susceptibility to pSjS, but the evidence still does not match that of other autoimmune conditions.²⁰ Several genome-wide association studies in pSjS have shown that the strongest association lies within human leukocyte antigen (HLA) genes.

 

The non-HLA genes IRF5 and STAT4 (relevant to the innate and adaptive immune systems) also show consistent associations but on a smaller scale.²⁰ These genes activate interferon (IFN) pathways as part of the innate immune system. Epigenetic mechanisms (e.g., DNA methylation) also play a role in pSjS pathogenesis by modulating gene expression without altering DNA sequences. This may serve as a dynamic link between the genome and SjS manifestation.

 

Chronic Immune System Activation

Chronic immune system activation is central to SjS pathophysiology. Innate (“nonspecific”) immunity is the defense system people are born with to protect them from all antigens (foreign substances) that enter the body. Unlike the innate immune system, which attacks based on identification of general threats, the adaptive immune system is activated by pathogen exposure. Adaptive immunity uses its “memory” to learn about the threat and enhance the immune system accordingly over time. The adaptive immune system relies on B cells and T cells—otherwise known as lymphocytes—to function.

 

IFNs exert antiviral, antimicrobial, antitumor, and immunomodulatory effects as part of the innate immune system. Literature widely recognizes the SjS-associated “IFN signature,” as increased IFN levels activate multiple IFN-responsive genes involved in immune activities.²¹ Research indicates that type 1 IFN dysregulation is a major pathogenic mechanism in many autoimmune conditions, including SjS.^21,22 It is also suggested that “crosstalk” between the type 1 IFN pathway and B-cell activation causes a vicious cycle of immune activation where type 1 IFNs drive production of autoantibodies (made against substances formed by a person's own body) which further promotes IFN production.²¹ Toll-like receptors (TLRs) also play key roles in the innate immune system.²¹ Research suggests that TLR-dependent IFN expression may contribute to immune system activation and autoimmunity development in pSjS.²¹

 

In patients with SjS, lymphocytes infiltrate the salivary and lacrimal glands and other glands of the respiratory and gastrointestinal tracts and vagina.⁴ T cells in this infiltrate produce interleukin (IL)-2, IL-4, IL-6, IL-1β, and tumor necrosis factor while the B cells cause hypergammaglobulinemia (overproduction of immunoglobulins/antibodies) and produce autoantibodies.⁴ Some of these autoantibodies target cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. About 60% of patients with SjS also express non-organ-specific autoantibodies, including rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes Ro/SS-A and La/SS-B.⁴ These processes eventually lead to glandular dysfunction that manifests as dry eyes and mouth and enlargement of major salivary glands.

 

B-cell activating factor (BAFF) may also contribute to pSjS development. BAFF is usually an active part of the innate immune system, but B cells, T cells, and epithelial cells in the salivary glands also release BAFF in response to IFNs.²¹ This suggests that epithelial cells are not only passive victims of pSjS autoimmunity but also contributors to immune system overactivation. This also shows that BAFF serves as a link between the innate and adaptive immune systems in pSjS and could also represent an important therapeutic target in pSjS.²¹

 

Other Theories

Research into a well-defined cause of SjS is ongoing. Additional theories include a potential viral trigger, neuroendocrine abnormalities, and autoimmune epithelitis. Evidence for a viral trigger in pSjS development is conflicting, but studies have been unable to replicate an association between SjS and Epstein-Barr virus, hepatitis C virus, retroviruses, or Coxsackie A virus.²¹ Researchers think that the microbial stimuli driving pSjS development could be diverse or that the initiating viral stimulus is no longer detectable once the disease manifests.

 

The classic triad of symptoms in pSjS is sicca, arthralgia, and fatigue. Pathogenic mechanisms producing fatigue remain unknown, but neuroendocrine dysfunction may play a key role in the process.²¹ Studies show that patients with pSjS have decreased hormone levels (e.g., cortisol) compared with healthy individuals, indicating dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is suggested to promote fatigue and depression in patients with pSjS.

 

The Search for Biomarkers

Disclosing a disease’s etiology allows researchers to identify biomarkers (i.e., a biological molecule in the body that is a sign of an abnormal process) for diagnosis and assessment of disease process and treatment response. It also stimulates discovery of treatment targets. Researchers have been hard at work searching for biomarkers for SjS. Biomarkers can drive more precise diagnosis and may be used to measure disease severity or see how well the body responds to treatment. Scientists have discovered potential biomarkers, but studies have yet to validate their utility in SjS diagnosis and treatment.

 

Novel tissue-specific autoantibodies (TSAs) have been described in the early stages of pSjS, including salivary protein-1, parotid secretory pro­tein, and carbonic anhydrase 6.²³ These are detectable even before the classic autoantibodies Ro/SS-A and La/SS-B. Further studies are needed to determine the utility of TSAs in screening patients with dry eye for SjS.

 

Some researchers hope to look beyond blood for reliable biomarkers for pSjS, more specifically in tears or saliva. They have studied tear proteins LACTO and LIPOC-1 as potential biomarkers for pSjS and one study shows they are more accurate indicators than traditional clinical tests for disease detection.²³ Other studies have examined salivary levels of S100A8/A9 as a potential biomarker for lymphoma development in patients with pSjS. Imaging biomarkers are also gaining attention. Salivary gland ultrasounds, for example, are non-invasive and valuable for studying the morphology (structure) of major salivary glands.²³

 

EVIDENCE-BASED TREATMENT STRATEGIES

SjS has no cure, and treatment varies from person to person based on their symptoms. Until recently, guidelines were unavailable to help clinicians manage Sjogren’s syndrome rationally.

 

In 2019, EULAR released evidence-based guidelines on which to rely, but clinicians may be unaware of its availability.¹¹ Medication is the cornerstone of these recommendations, so pharmacists and pharmacy technicians should be prepared to make evidence-based recommendations and appropriate referrals to improve care for patients with SjS. It is important to remember that no therapy is explicitly approved for SjS disease modification. Rather, providers use therapies indicated for each symptom separately—and some off-label (i.e., for a non-FDA-approved indication)—on a trial-and-error basis based on available evidence from small trials that sometimes include a subset of patients with SjS.

 

Sicca

Glandular dysfunction—the cause of sicca symptoms—appears to be stable for long periods of time (up to 12 years) and has a chronic course in patients with pSjS.¹¹ No therapeutic intervention can reverse or slow the progression of glandular dysfunction, so sicca symptoms cannot be cured. EULAR guidelines state that the first therapeutic approach to sicca symptoms should be symptomatic relief using topical therapies (e.g., saliva substitutes, artificial tears).¹¹ This minimizes the risk of adverse effects (AEs) seen with systemic therapies.

 

Finding the optimal lubrication is a matter of trial and error, so pharmacy staff should be prepared to set realistic expectations for patients seeking relief of sicca symptoms. They should also help patients recognize when it may be time to talk to their prescriber about stepping up to pharmacologic treatment.

 

Oral Dryness

Treatment of oral dryness depends on the severity of salivary gland dysfunction (Figure 1).¹¹ No evidence indicates any non-pharmacologic stimulant is better than another, so patients with mild glandular dysfunction should use a trial-and-error approach to find one that works for them. If these therapies don’t help or patients do not wish to use non-pharmacologic stimulants, providers should move on to pharmacologic stimulation. Muscarinic agonists’ main AE is excessive sweating.¹¹ To avert this, EULAR recommends increasing the dose progressively up to 15 to 20 mg/day when possible.

 

Cevimeline and pilocarpine are cholinergic agents, meaning they activate muscarinic receptors in the parasympathetic nervous system (which controls bodily functions when a person is at rest) to stimulate saliva production. Patients with SjS take cevimeline 30 mg by mouth three times daily or pilocarpine 5 mg by mouth four times daily to treat dry mouth.^24,25 The most common AEs of cevimeline and pilocarpine are excessive sweating, nausea, rhinitis (stuffy nose), and diarrhea.

 

The ideal saliva substitute will have a neutral pH mimicking natural saliva composition and contain fluoride and other electrolytes.¹¹ Gel formulations are ideal for patients with acceptable salivary flow output, especially those with oral dryness at night. However, patients often dislike these formulations due to their sticky mouthfeel. Pharmacists can recommend that patients dilute oral gel formulations to reduce this phenomenon for better adherence. Thinner preparations are preferred for patients with better-preserved glandular function.¹¹

 

Some experts feel that all patients with oral dryness should use salivary substitutes regardless of the degree of glandular dysfunction.¹¹ Whether patients use these formulations or not, all patients with salivary dysfunction should use a neutral pH sodium fluoride gel to prevent extensive caries (i.e., cavities).

 

Ocular Dryness

Reflex tears are the tears we produce when we cry, while we produce basal tears continuously to lubricate the ocular surface (the surface layers of the eye, namely the cornea and conjunctiva).²⁶ While tears may taste like salt water, their composition is more complex. Both types of tears contain water, but they also contain mucin, lipids, proteins (lysozyme, lactoferrin, lipocalin, immunoglobulins, and peroxidase), electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, and calcium), growth factors (epidermal growth factor), cytokines, and glucose.

 

Artificial tears and ocular gels/ointments are first line therapies for volume replacement and lubrication for ocular dryness.¹¹ While many people refer to over-the-counter (OTC) drops, gels, ointments, and lubricants as artificial tears, these products lack the biologically active components found in natural tears.²⁷ Their primary role is to supplement the patient’s natural tear production and provide sufficient lubrication to avoid eye complications.

 

Many artificial tear formulations are available, so patients may need assistance navigating the options. Table 2 lists common ingredients in artificial tears and their functions. A major difference between OTC products is the presence of chemical formulations that increase viscosity (thickness/stickiness) and adhesion and facilitate even distribution across the ocular surface.²⁷ As a general rule, drops are the lowest viscosity products, ointments have the highest viscosity, and suspensions fall in between. Lubricants with a polymeric base or viscosity agent are preferred for patients with SjS to¹¹

1. Add volume to the tear lake
2. Increase the time the lubricant remains on the ocular surface
3. Cushion the ocular surface to reduce friction between the eye and the eyelid

 

Table 2. Artificial Tear Ingredients and Their Functions^27-30

Ingredient Class	Function	Examples
Astringent	Precipitate protein to clear mucus from outer eye surface	zinc sulfate
Buffering agent	Maintain normal tear film pH	bicarbonate, phosphate
Demulcent	Protect and lubricate mucous membrane surfaces	carboxymethylcellulose sodium, dextran, gelatin, glycerin, hydroxyethyl cellulose, hypromellose, methylcellulose, polyethylene glycol, polysorbate, polyvinyl alcohol, povidone, propylene glycol
Lipid formulations	Improve gland function and increase tear film stability	castor oil, phospholipids, triglycerides
Preservatives	Prevent bacterial contamination	benzalkonium chloride (BAK), ethylenediaminetetraacetic acid (EDTA), polyquaternium-1, sodium chlorite, sodium perborate

 

 

Not all artificial tear products are equal, and different products work better for different patients. The optimal artificial tear offers long-lasting, effective symptom relief. It should also have low blur and be comfortable to administer.³¹ Surface tension, pH, viscosity, duration of action, and preservative presence or absence affect these factors.

 

OTC eye drops commonly include preservatives to prevent bacterial contamination. Repeated use of preservative-containing eye drops is associated with ocular allergies and toxicities, which can lead to product nonadherence and worsening symptoms.²⁷ Benzalkonium chloride (BAK)—the most common preservative used in eye formulations—is an epitheliotoxin and a toxic detergent.^28,29 It attracts monocytes and lymphocytes to the conjunctiva, worsening inflammation and thickening the tissue. This effect is cumulative; the more the eye is exposed to BAK, the greater the negative effects.²⁹ As a rule-of-thumb, pharmacists should always recommend products without BAK as a preservative.²⁸

 

EULAR recommends that all patients with SjS who present with ocular dryness use artificial tears containing methylcellulose or hyaluronate at least twice daily.¹¹ They should increase frequency as symptoms reappear as often as hourly. Individuals who use artificial tears four or more times daily should always use preservative-free products. Patients who experience overnight dryness should consider ophthalmic ointments before bedtime, as they remain in the eye longer. These are not recommended for daytime use because they blur vision.

 

Patients who are refractory to artificial tears and ointments—those who do not improve after maximum use—should see an ophthalmologist for prescription treatment. Short-term non-steroidal anti-inflammatory drug (NSAID) or corticosteroid eye drops are indicated for a maximum of two to four weeks.¹¹ This is due to the potential for AEs with long-term use, including

• NSAIDs: corneal-scleral melts, perforation, ulceration, severe keratopathy
• corticosteroids: infections, increased intraocular pressure, cataract worsening or development

 

Cyclosporine 0.05% is another therapeutic option for patients who are refractory to or do not tolerate artificial tears and ointments and those with severe ocular dryness requiring multiple courses of a glucocorticoid eye drop.¹¹ Cyclosporine is a calcineurin inhibitor that prevents T cell maturation.³² This counteracts SjS’s vicious cycle of inflammation. Patients administer the drug in the eyes twice daily, and the most common AEs are eye burning, stinging, and irritation. Of note, a small trial investigating topical tacrolimus showed promising results, but larger trials are needed to confirm the role of this drug for SjS-associated ocular dryness. Some providers also use lifitegrast ophthalmic solution or varenicline nasal spray off-label to treat SjS-associated dry eye, but EULAR makes no recommendation for their use.

 

Serum eye drops are blood-derived eye drops that may be autologous (uses the patient’s own blood) or allogenic (the blood comes from a donor).²⁶ These are compounded; a specialized pharmacy collects the patient’s blood, then clots, centrifuges, and dilutes it with sterile saline. The serum drops also contain increased concentrations of proteins, growth factors, vitamins A and C, antioxidants, and electrolytes found in natural tears.²⁶ This is meant to mimic natural basal tears’ biochemical properties to heal the cells of the ocular surface.

 

Small uncontrolled studies have examined serum eye drops for SjS patients, and results are inconsistent.¹¹ Nevertheless, ophthalmologists may use this option for patients with severe symptoms who are refractory to topical cyclosporine drops. When considering serum eye drops, individuals should consider storage needs, as they should be frozen until use (up to six months) and then refrigerated once opened for up to one week. Contamination during and after the compounding process is also possible.¹¹

 

Studies have investigated the utility of other therapies—hydroxychloroquine, immunosuppressive agents, and rituximab—for SjS-related ocular dryness, but EULAR does not recommend any of them for ocular dryness alone based on available clinical data.

 

Fatigue and Pain

Patients with pSjS often present with general non-inflammatory joint/muscle pain and fatigue/weakness. After ruling out potential concomitant conditions (e.g., osteoarthritis, hypothyroidism, vitamin deficiencies, depression), providers should evaluate whether the patient is experiencing joint pain (arthralgia) or joint inflammation (arthritis, tenosynovitis).¹¹ The ESSDAI score defines low articular activity level as arthralgia in the hands, wrists, ankles, and feet accompanied by morning stiffness longer than 30 minutes, always ruling out concomitant osteoarthritis.¹⁷ Objective inflammation (i.e., redness, heat, and swelling) in one or more joints is considered arthritis, and the ESSDAI score classifies arthritis severity based on the number of joints involved. Management of arthritis is covered under systemic disease treatment, and Table 3 outlines EULAR recommendations for non-arthritis musculoskeletal pain.

 

Table 3. EULAR-Recommended Management of SjS-Associated Musculoskeletal Pain*¹¹

Acute Pain	Frequent Acute Pain	Chronic, Daily Pain
· Acetaminophen or NSAIDs for symptomatic relief for up to 7 to 10 consecutive days · Topical diclofenac may be effective for local pain with fewer adverse effects	· Consider hydroxychloroquine in patients with articular pain based on its evidence for use in other SAD · Off-label use of biologics (even as rescue therapy) is not recommended	· Emphasize non-pharmacologic management (e.g., physical activity) before medications · Goal is to avoid repeated use of NSAIDs or glucocorticoids · Musculoskeletal: antidepressants and anticonvulsants · Neuropathic: gabapentin, pregabalin, or amitriptyline · Opioids are not recommended

*Providers must first rule out concomitant osteoarthritis (i.e., objective inflammation in 1 or more joints); NSAID = non-steroidal anti-inflammatory drug; SAD = systemic autoimmune diseases

 

Systemic Disease

EULAR defines systemic SjS as disease involvement that affects or has affected any of the organs/systems included in the ESSDAI score (i.e., all domains except biological).¹¹ Systemic disease is linked to autoimmune dysfunction that may eventually become irreversible. Providers should limit systemic therapies to patients with active systemic disease following careful evaluation of symptom severity and organ damage. Clinicians should consider systemic therapy on an individual basis, as not all patients with active systemic disease will require it.¹¹

 

EULAR makes a few general recommendations regarding systemic therapy¹¹:

1. Consider systemic therapies for most patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score (i.e., greater than 5).
2. Therapeutic response is considered a reduction of 3 or more points in the global ESSDAI score.
3. Providers should follow a sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics to treat organ-specific systemic manifestations.
4. Use glucocorticoids at the minimum dose and duration necessary to control active systemic disease.
5. Use synthetic immunosuppressive agents (e.g., azathioprine, cyclophosphamide, leflunomide, methotrexate, mycophenolate) mainly as glucocorticoid-sparing agents in patients requiring long-term glucocorticoid therapy (i.e., those with severe organ impairments).
6. Consider B-cell targeted therapies (e.g., belimumab, rituximab) in patients with severe, refractory systemic disease.

 

Evidence regarding the use of glucocorticoids for SjS is weak and studies report high rates of AEs.¹¹ Guidelines recommend administering pulses of methylprednisolone followed by doses of 0.5 mg/kg daily or less as induction therapy in patients with severe disease and lower doses in patients with less severe disease. The goal is to withdraw glucocorticoids in patients whose SjS becomes inactive as soon as possible or at least target a maintenance dose of 5 mg daily or less with the aid of steroid-sparing immunosuppressive agents.¹¹ Studies of immunosuppressive agents are lacking, so EULAR does not recommend one agent over another, except in the case of patient characteristics or comorbidities. Dose, route of administration, and duration of treatment are not established given the lack of clinical data, so physicians should follow similar dosing schedules to other systemic autoimmune diseases.¹¹

 

EULAR guidelines also include algorithms for each ESSDAI domain based on available trial data and the clinical experience of the individuals on the EULAR task force.¹¹ Figure 2 summarizes these recommendations, including standard of care, second line, and third line recommendations.

 

Considering Comorbidities

More than 20% of people with SjS are older than 65 years, making them more likely to have pulmonary, liver, kidney, or heart-related comorbidities.¹⁹ It is especially important to consider alternative causes of sicca in older patients since many conditions and drugs produce oral and ocular dryness. Older people are nearly twice as likely to suffer from dry eyes than younger individuals.¹⁹ Older age is also associated with decreased salivary flow rate. Dry mouth is more than a bothersome symptom. Addressing dry mouth in older adults is vital because worsening oral health increases risks of malnutrition, social isolation, care dependency, and frailty that tend to affect this population.¹⁹

 

An estimated 45% to 80% of the older adult population reports some pain, most commonly musculoskeletal.¹⁹ Treatment plans for these patients should emphasize non-pharmacologic relief rather than medications as first-line therapy. Also, despite the lack of available evidence, experts suggest that topical NSAID formulations may be effective for local SjS-related pain in older adults with fewer AEs than oral NSAIDs.¹⁹

 

Treating systemic symptoms in this population also requires special considerations. Older adults are more likely to experience AEs from glucocorticoids—including blood clots, osteoporosis, and bone fractures—than younger individuals.¹⁹ Pharmacists should also consider the greater frequency of hepatic and renal impairment in older patients. For example, renal function decline and decreased folate stores may increase methotrexate-related toxicity.¹⁹ Studies suggest that disease-modifying antirheumatic drugs (including some biologics) have similar effects on younger and older patients while maintaining favorable AE profiles.¹⁹ Older people, therefore, should not be excluded from the use of these agents for systemic disease where appropriate.

 

Autoimmune conditions increase the risk of lymphoma, cancer stemming from the lymph nodes.³³ More specifically, pSjS is the autoimmune disease associated with the highest risk of B-cell lymphoma, occurring in 5% to 10% of patients.³³ This risk increases by 2.2% per year of age in this population.³³ In patients with pSjS, chronic stimulation of autoimmune B cells leads to development of B-cell lymphoma. Screening for lymphoma is an important part of a comprehensive treatment plan given the increased risk. Similar to other autoimmune conditions, SjS also increases patients’ risk for atherosclerosis and coronary artery disease.²²

 

Research Continues

Researchers continue to define new therapeutic targets and investigate new treatments for SjS. Targeting B cells appears to be the most promising therapeutic approach for this condition.¹⁸ Studies are evaluating anti-CD20 antibodies and antibodies targeting the BAFF signaling pathway to target B cells and anti-CD40 antibodies to block the crosstalk between T cells and B cells.¹⁸ So far, two agents have met their primary outcome—improvement in systemic disease activity—in pSjS clinical trials: anti-BAFF receptor antibodies and anti-CD40 antibodies.

 

BAFF receptors are exclusively expressed on B cells, so targeting these receptors effectively depletes B cells to blunt the autoimmune response in pSjS. Clinical trials have assessed an anti-BAFF receptor antibody, ianalumab (VAY736) in patients with pSjS with positive results.^34,35 In the phase 2b study, patients experienced improved ESSDAI scores from baseline to week 24 and improvement in stimulated saliva flow rate.³⁵ This is a promising option for a future disease-modifying pSjS treatment, and phase 3 trials are ongoing.

 

The interaction between CD40 and the CD40 ligand (CD40L) is important for B cell development, antibody production, and optimal T cell-dependent antibody responses. Patients with pSjS have increased expression of CD40L compared to healthy individuals, which suggests that CD40-CD40L interactions could be a practical target for pSjS treatment.¹⁸ Phase 2 studies have shown promising results for iscalimab, an anti-CD40 antibody, to treat pSjS. Patients treated with intravenous iscalimab experienced a mean ESSDAI score decrease of 5.21 points, a significant improvement over patients in the placebo group.³⁶ Phase 3 studies of this therapy are forthcoming. A phase 2 trial of another anti-CD40L antibody is also underway.³⁷

 

Additional therapeutic targets under investigation include¹⁸

• Bruton’s tyrosine kinase, an important molecule in B cell receptor signaling
• plasmacytoid dendritic cells, which secrete type 1 IFNs
• downstream type 1 and 2 IFN signaling (using Janus kinase inhibitors)
• IL-12 signaling pathway and induction of T helper 1 cells, which secrete type 2 IFNs (using ustekinumab)

PAUSE AND PONDER:  How often do you encounter patients asking for help choosing artificial tear products? What could you improve about your ability to assist them?

MULTIDISCIPLINARY TEAM CARE IS IDEAL

EULAR guidelines recommend a multidisciplinary approach to SjS treatment.¹¹ This is the second strongest recommendation included in the 2020 guidelines, with only a recommendation for patients who develop B-cell lymphoma to receive individualized treatment receiving a stronger grade. SjS’s overall prevalence in the general population is low and the condition presents differently in every patient, making it difficult for any one provider to ensure in-depth expertise in managing it. At minimum, the SjS care team should include a primary care provider (PCP), a rheumatologist, a dentist, and an ophthalmologist. Pharmacy staff should understand the roles and responsibilities of each provider to better recognize their own place on the care team.

 

Rheumatologist

Rheumatologists are usually the “lead” of the medical team for SjS and have the primary responsibility for managing it.³⁸ The rheumatologist should verify the diagnosis, including looking for disease mimics and screening and monitoring for coexisting rheumatologic or autoimmune conditions. They should also screen for lymphoma risk factors and common comorbidities. They may collaborate with the patient’s PCP for comorbidity monitoring and management. Rheumatologists also provide treatment for systemic features of SjS.³⁸

 

Primary Care Provider

The PCP should provide routine, comprehensive health care addressing a wide range of issues, including patients’ mental health.³⁸ They should collaborate with the patient’s rheumatologist to establish who is responsible for overlapping areas of practice (e.g., comorbidities, immunizations, nutrition concerns). Screening for comorbidities—including cardiovascular disease, osteoporosis, sinusitis, and others—is an important task for PCPs, but they may be unaware of the increased risk of these conditions in patients with SjS. Pharmacy teams should encourage patients to advocate for themselves, and direct patients to www.sjogrensadvocate.com for advice on how to do so effectively.³⁸

 

Ophthalmologist

Ophthalmologists are responsible for managing severe dry eye.³⁸ Occasionally, the ophthalmologist is the first provider to suspect SjS and refers patients to rheumatology for general management. They perform diagnostic tests (e.g., Schirmer’s test, ocular staining score, tear breakup time) to determine the severity of SjS ocular symptoms and blood tests to screen for biologic signs of SjS. These clinicians also provide routine dry eye management, including prescription medications/drops and recommendations for OTC therapies.

 

Dentist

Many patients with SjS require extensive dental care exceeding the recommended checkups every 6 months for otherwise healthy individuals.³⁸ Preventative dental visit frequency depends on patients’ level of dryness and decay. At every checkup, dentists should examine the entire oral region, including palpating (i.e., feeling with the fingers) salivary glands, face, and neck for swelling and masses.³⁸ They should also provide dental caries prevention, screening, and treatment.

 

Where Pharmacy Fits In

Most often, pharmacy technicians will encounter patients with SjS at the pickup counter, so they should be prepared to refer patients to the pharmacist when appropriate. Sometimes, patients request assistance finding the eye care aisle for OTC drops. Before pointing them in the right direction, pharmacy technicians should refer patients to the pharmacist for counseling if they indicate they are new to using artificial tears (e.g., asking your opinion about product selection).

 

Technicians can also help patients locate products based on pharmacist recommendations and provide informational handouts about proper administration technique (see Sidebar). While cost is an important factor in therapy adherence, consider recommending name brand products rather than store brand generics whenever feasible. While the active ingredients may be consistent across proprietary and store brand products, the concentration of these components is often less than 5% of each drop.³⁹ The amount of inactive ingredients (i.e., “filler”) differs from brand to brand.

Sidebar: Don’t Leave Patients High and Dry^40,41

To provide maximum relief, patients must administer eye formulations correctly. Many patients struggle with this, especially older patients, and joint pain in SjS can make it even more difficult. Counseling patients on proper eye drop and ointment instillation is crucial to improving outcomes.

 

Eye Drop Administration

1. Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses unless the product is specifically designed for use with contact lenses. If using a suspension, shake well.
2. Tilt head back, gently grasp the lower eyelid below lashes and pull away from the eye to create a pouch.
3. Look up and administer a single drop into the pouch without touching the tip of the container to the eye.
4. As soon as the drop is instilled, release the eyelid slowly. Close eyes gently for 3 minutes and position the head downward (gravity pulls the drop onto the ocular surface). Minimize blinking or squeezing the eyelid.
5. Use a finger to gently apply pressure to the opening of the tear duct (inner corner of the eye) to prevent medication from draining through the tear duct and increase medication contact time in the eye.
6. If additional ophthalmic therapy is indicated, wait 5 to 10 minutes in between. Also, wait 5 to 10 minutes before reinserting contact lenses, if applicable.

 

Pro-Tip: tell patients, “If you have a hard time deciphering whether you’ve successfully installed eye drops, refrigerate the solution before administration to detect the drops more easily on your eye’s surface. Do NOT use this trick with a suspension.”

 

Eye Ointment Administration

1. Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses unless the product is designed for use with contact lenses specifically.
2. Tilt head back, gently grasp the lower eyelid below lashes, and pull away from the eye to create a pouch.
3. Look up, and with a sweeping motion, place a strip of ointment ¼ to ½ inch wide inside the lower eyelid by gently squeezing the tube (avoid touching the tube tip to any tissue surface).
4. Release the eyelid slowly and close eyes gently for 1 to 2 minutes.
5. Vision may blur temporarily, so avoid activities that require good visual acuity until vision improves. Also, wait 15 minutes before reinserting contact lenses, if applicable.

 

Clearly, a medication expert needs to contribute to patient and provider education and oversee prescribed and OTC medications. Pharmacists can offer various clinical pearls to help patients with SjS avoid dry eyes, mouth, and skin.

 

Lifestyle modifications⁴²:

• Avoid windy or drafty environments and wear sunglasses outdoors
• Use a humidifier indoors to keep the air moist
• Practice good oral hygiene (e.g., chew sugarless gum, stay well hydrated, see a dentist three times a year)
• Consciously remember to blink when working at a computer or reading extensively
• Avoid wearing eye makeup
• Consider smoking cessation and avoid smoky environments
• After showering, pat dry gently and apply an emollient to damp skin within three minutes

 

Separation and timing^40,41:

• Separate administration of multiple eye drops by at least 5 minutes to ensure the first drop is not flushed away by the second and the second drop is not diluted by the first
• If using multiple products, use them in order of least viscous to most viscous to ensure efficacy of all treatments
• If using drops and ointment, administer drops at least 10 minutes before ointment so the ointment does not create a barrier to the drops’ absorption
• If using a suspension with another dosage form, use the suspension last because its retention time in the tear film is longer

 

Pharmacists and pharmacy technicians should also be aware of medications that could worsen symptoms of dryness (Table 4). Technicians should refer patients with SjS to the pharmacist when they see these at the pick-up counter. They should also stay up to date on available eye care formulations and discuss new products with the pharmacist. Pharmacists should counsel patients with SjS about which OTC products to avoid and offer to contact prescribers to recommend prescription therapy changes.

 

Table 4. Medications That Cause or Worsen Ocular Dryness^19,25,28

Medication/Class	Examples	Rx/OTC	Mechanism for Ocular Dryness
Anticholinergics	benztropine trihexyphenidyl	Rx	Blocking acetylcholine blurs vision and stops the signals that normally tell the eyes to produce tears
Antihistamines (especially first-generation)	cetirizine chlorpheniramine diphenhydramine loratadine	OTC	Dry secretions (including tears) and produce anticholinergic adverse effects
Beta-blockers	atenolol metoprolol propranolol	Rx	Cause the body to make less of a protein present in tears, and can lower pressure in the eyes, affecting the amount of water in the tears
Decongestants	phenylephrine pseudoephedrine	OTC	Decrease nasal/mucosal mucus production (including the eyes), which decreases tear production
Diuretics	furosemide hydrochlorothiazide	Rx	Help the body eliminate water and salt, which can alter tear composition
Hormones	estrogen/progesterone and other hormones used for contraception, infertility, or hormone replacement	Rx	Unknown
Isotretinoin	N/A	Rx	Lessens oil production by certain glands to treat acne, but some of those glands are in eyelids, decreasing oil in tears
Tricyclic antidepressants	amitriptyline amoxapine clomipramine imipramine maprotiline	Rx	Anticholinergic adverse effect stops the signals that normally tell the eyes to produce tears

OTC = over-the-counter; Rx = prescription only

 

CONCLUSION

SjS is a complex, multifactorial condition that impacts patients’ quality of life substantially. Providing optimal care for this disease requires a multidisciplinary team, on which pharmacists and pharmacy technicians provide a link between all providers to ensure continuity of care. Recognizing patients with SjS in the pharmacy is crucial to prevent polypharmacy, ensure patients know how to use eye care formulations, assist patients in finding OTC products to address symptoms, and refer to other providers when necessary. This will improve care and outcomes for patients with SjS.

 

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