Dealing with the high cost of biological therapies: developing and implementing a biological therapy prioritization protocol for ankylosing spondylitis patients in a tertiary hospital.

OBJECTIVE: In January 2011, a biological therapies commission was created in our hospital to fully address the management of biological drugs. A biological therapy prioritization protocol was developed for ankylosing spondylitis (AS) patients. Here, we describe it and report on its economic impact to illustrate how we are optimizing the use of these expensive new drugs. METHODS: The biological therapies commission established several procedures for the rational use of biological drugs such as cost-efficiency therapeutic protocols, pharmacovigilance, and therapeutic drug monitoring programs. The AS protocol was based on clinical and economic aspects. We estimated the economic impact of the protocol by comparing the cost of treating AS patients with biological drugs in the pre-commission (2009 - 2010) vs. post-commission period (2011 - 2013). AS patients treated with adalimumab (ADA), etanercept (ETN) or infliximab (IFX) for at least 6 months in the 2009 - 2013 period were included. RESULTS: 107 patients were included. In the pre-commission period, total expenses increased by +30,944 Euro (+4%). After protocol implementation, total expenses decreased by 11,441 Euro (-1%) during 2011, and by an additional 36,781 Euro (-4%) and 53,872 Euro (-8%) in 2012 and 2013, respectively. In the 2010 - 2013 period the cost of biological therapy per patient-year decreased by 869 €, suggesting the positive effects of the biological therapy prioritization protocol instauration. CONCLUSION: We describe the establishment of a multidisciplinary biological therapy commission to optimize the use of biological therapies. We illustrate its work in developing a protocol for the management of AS patients with such therapies. We show that after 3-years of implementation, the biological therapy prioritization protocol allowed us to steadily decrease the direct cost of biological drug therapies per patient, up to 869 Euro.

Effectiveness of infliximab, adalimumab and golimumab for non-infectious refractory uveitis in adults.

AIM: To discuss the available data regarding the off-label uses of anti-TNF agents in non-infectious uveitis. DATA SOURCE: A literature search was performed in Medline through PubMed from January 2001 to January 2014. STUDY SELECTION AND DATA EXTRACTION: English-language articles about uveitis treatment with anti-TNF drugs in adult patients were reviewed. DATA SYNTHESIS: The use of anti-TNF-Î ± drugs for treatment of several refractory manifestations of refractory uveitis in adult patients is increasing. However, due to the lack of evidence from randomized controlled trials, the use of anti-TNF in uveitis remains “off-label” in most countries. There is no trial-based evidence to support it except for the experience provided by cases and case series. This experience, which is continuously increasing, has yielded encouraging results. Anti-TNF-Î ± drugs, such as infliximab, adalimumab, and golimumab, are reasonably effective for controlling ocular inflammation and sparing patients corticosteroid treatment in non-infectious refractory uveitis. Approximately 80% of patients on infliximab, adalimumab, or golimumab were able to achieve sustained control of inflammation by 6 months. CONCLUSION: Anti-TNF-Î ± therapy is effective in inducing clinical remission for refractory uveitis, with a relatively low rate of treatment-ending adverse events. However, randomized and controlled trials are required to adequately assess the maintained clinical efficacy and safety profile in the long term of anti-TNF agents for non-infectious refractory uveitis.

Economical impact associated with a biological therapy prioritization protocol in patients with rheumatoid arthritis in the Hospital of Sagunto.

BACKGROUND: Until 2010 the cost of biological treatments in Rheumatoid Arthritis (RA) was increasing annually by 15% in our hospital. In 1st January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs and a biological therapy prioritization protocol in RA patients was also established to improve the efficient usage of biological drugs in RA. OBJECTIVE: To evaluate the economic impact associated with a biological therapy prioritization protocol for RA patients in the Hospital of Sagunto. METHODS: Observational, ambispective study comparing the associated cost of RA patients treated with biological drugs in the pre-protocol (2009 - 2010) versus post-protocol periods (2011 - 2012). RA patients treated with Abatacept (ABA), Adalimumab (ADA), Etanercept (ETN) or Infliximab (IFX) for at least 6 months during the study period (2009 - 2012) were included. In 2012, Tocilizumab (TCZ) was also included in the prioritization protocol. Prioritization protocol was established based on both clinical and economical aspects and supervised case by case by our Commission. Cost savings and economic impact were calculated using Spanish official prices. RESULTS: In the pre-protocol period (2009 - 2010), total expenses were increasing by €110,000, up to €1,761,000 in 2010 (€11,362 pat/year). After protocol implementation, total expenses decreased by 53,676€ on the 2010 - 2011 period, and 149,200€ on the 2011 - 2012 period. On the 2010 - 2011 period the cost of biological therapy per patient-year decreased 355€ (11,007€ pat/year) and additional 653€ (up to 10,354€ pat/year) by 2012, with a cumulative effect of the protocol implementation of 1,008€ per patient-year. In the pre-protocol period (2009), the annual cost/patient was 10.812€ with ETN, 10.942€ with IFX, 12.961€ with ADA and 12.739€ with ABA. By 1st January 2013, the annual cost per patient was 9,469€ with ETN, 10,579€ with IFX, 11,117€ with ADA, 13,540€ with ABA and 14,932€ with TCZ. CONCLUSIONS: The creation of our Commission of Biological Therapies is key to rational management of RA patients and optimization of resources, allowing us to save 200,000€ after 2-year efficiency protocol implementation.

Clinical and economic impact of the use of etanercept 25 mg once weekly in rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis patients.

OBJECTIVE: To determine the clinical and economic impact of etanercept 25 mg/week (ETN25) on rheumatoid arthritis (RA), psoriatic arthropathy (PA) and ankylosing spondylitis (AS) patients in sustained clinical remission. METHODS: Observational, retrospective cohort of patients treated with etanercept 50 mg/week (ETN50) who achieved and maintained clinical remission (Disease Activity Score 28 < 2.6 or BASDAI < 2) over a period of 1 year and had slow worsening of structural changes were enrolled in an off-label program (January 2006 to June 2013) to switch from ETN50 to ETN25. Economic impact was assessed using Enbrel® official prices for Spain. RESULTS: From 1 January 2006 to 1 June 2013, 98 RA, 40 PA and 47 AS patients were treated with ETN50; 39 (24%) patients (20 women; age = 53 ± 7 years; 24 RA, 7 PA, 8 AS) received ETN25 for at least 0.5 years (2.6 ± 2.0 years; range = 0.5 - 7.3 years). As of 1 June 2013, 29 (74%) patients continued on ETN25. RA patients: 17 patients continued on ETN25, 5 patients discontinued use due to reactivation of RA (4 switched back to ETN50 and 1 switched to adalimumab; all regained clinical remission) and 2 patients discontinued use due to adverse reactions. PA patients: four patients continued on ETN25, two patients discontinued use due to reactivation of PA (switched back to ETN50, regaining clinical remission) and one patient discontinued use due to adverse reaction. All AS patients continued on ETN25. The total savings associated with ETN25 over the 7-year observation period were €622,073, resulting in the ability to treat 52 additional patients with ETN50 for one year without increasing total ETN costs. CONCLUSION: ETN25 produces cost savings while maintaining clinical response in a high proportion of patients after at least one year under clinical remission with ETN50. At a time when the cost of therapy is an unavoidable component of healthcare treatment decisions, ETN25 could be a cost-effective option for selective RA, PA and AS patients.

Educational session as a tool to increase patient satisfaction of switching etanercept from the prefilled syringe to the autoinjection pen.

OBJECTIVE: To assess patients' acceptability of switching etanercept from the prefilled syringe to the autoinjection pen in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis patients. METHODS: A two-phase cross-sectional study was designed. First phase: consisted of a 2 h information/education session to present the pen and learning its use. At the end of the session, patients completed a self-administered questionnaire regarding the meeting usefulness. Second phase: eight single-use prefilled Enbrel® Pen Myclic were provided. RESULTS: The number of patients included were 104 (rheumatoid arthritis 58, psoriatic arthritis 31, ankylosing spondylitis 15). Attendees showed a high satisfaction degree with the meeting. A high percentage of patients (74.4 - 95.1%) rated the items of the questionnaire as 'very much'. Patients reported > 95% adherence to etanercept autoinjection pen. The percentage of patients self-administering etanercept increased from 66 to 94% and the percentage of those attending primary care for injection decreased from 23 to 2%. It produced important cost savings, in our study represents > 22.000 euros/year. Pain at the injection site was significantly reduced with the use of autoinjection pen. Ninty seven (93%) patients considered that the use of the autoinjection pen was easier than the syringe and 94.2% chose the pen as their preferred delivery system. CONCLUSIONS: The autoinjection pen is an advantageous delivery option for etanercept. This study provides further evidence to support that the education strategy is a valid method for switching anti-TNF-α drugs from syringe to pen in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Acceptability of switching adalimumab from a prefilled syringe to an autoinjection pen.

OBJECTIVE: To assess patients' acceptance of switching adalimumab from a prefilled syringe to an autoinjection pen. METHODS: A two-phase cross-sectional study. The first phase consisted of a 2-h information/education session to present the pen and assist patients in learning its use. At the end of the session, patients completed a self-administered questionnaire regarding usefulness of the meeting. At the next hospital pharmacy dispensing visit the autoinjection pen was provided. Four single-use prefilled devices (40 mg/0.8 ml every other week) were provided. RESULTS: The study population included 55 patients (rheumatoid arthritis 29, psoriatic arthritis 17, ankylosing spondylitis 9). Attendees showed a high degree of satisfaction with the education session (between 72.7 and 90.9% rated the relevant items of the questionnaire in the highest category). Fifty-one patients participated in the second phase of the study. Patients reported 100% adherence to treatment with the autoinjection pen. The percentage of patients self-administering medication increased from 51 to 84% and the percentage attending primary care for injection decreased from 33 to 2%. Pain at the injection site was significantly reduced with the use of the autoinjection pen. The mean (sd) visual analogue scale (VAS) score was 3.52 (2.26) for the syringe compared with 2.02 (2.16) for the pen (p < 0.001). Forty-four (86.3%) patients considered that the use of the autoinjection pen was easier than the syringe, and 96.1% chose the pen as their preferred delivery system. CONCLUSIONS: This study provides further evidence to support the use of the autoinjection pen as a delivery option for adalimumab therapy.

Urticaria due to etanercept in a patient with psoriatic arthritis.

A 50-year-old woman was referred to our emergency room because of urticaria. Eleven days after etanercept therapy was started, the patient developed an urticarial rash of the trunk and face. A diagnosis of generalized urticaria was made. Etanercept treatment was suspended. Treatment was started with methylprednisolone and dexchlorpheniramine. The patient's condition improved and she was discharged. In this case, the most probable cause of urticaria was considered to be etanercept because of the temporal relationship between exposure to the drug and the onset of symptoms. The adverse reaction could be considered probable. Although the overall risk of skin adverse events associated with etanercept appears low, clinicians should be aware of this reaction.

Generalised erythematous skin eruptions induced by sorafenib: cutaneous toxicity and treatment outcome.

A woman diagnosed of a renal cell carcinoma in 1989 had a metastatic kidney cancer localised in subcutaneous nodules, gut and lung in 2007. Sorafenib treatment was initiated a 400 mg orally twice a day. The patient developed generalised erythematous skin eruptions and two weeks later a widespread erythematous maculopapular eruption located exclusively on the legs and arms, along with an objective response. The most likely cause of the generalised erythematous skin eruptions was considered to be sorafenib because of the close temporal relationship between exposure to the drug and onset of symptoms. Furthermore, a relationship between sorafenib skin toxicity and treatment efficacy was observed. This therapeutic efficacy of EGFR inhibitors and cutaneous side effects should be better assessed in large cohorts or trials to determine whether the skin toxicity of patients can be linked to an objective antitumour response.

Severe myalgia associated with adalimumab treatment in a patient with Crohn's disease.

OBJECTIVE: To report a case of severe myalgia associated with adalimumab in a patient with Crohn's disease. CASE SUMMARY: A 44-year-old woman was diagnosed as having ileocecal Crohn's disease with perianal fistula lesions. She was treated with 3 infusions of infliximab 5 mg/kg, which stabilized her condition. However, when reactivation of Crohn's disease occurred, infliximab was discontinued. Eight weeks after infliximab was suspended, treatment with adalimumab was started, with an initial dose of 160 mg followed by 80 mg in week 2; 48 hours after the first dose, the woman complained of generalized severe pain in her upper and lower extremities. Results of all laboratory tests were within normal limits. A diagnosis of severe drug-related myalgia was made. We suspected that adalimumab was the causative agent since it was the only drug that had been added before the musculoskeletal symptoms appeared. Adalimumab was stopped and treatment with ibuprofen and tramadol was started. Fifteen days after stopping adalimumab, the patient reported complete resolution of her muscle pain. DISCUSSION: Myalgia following administration of adalimumab is uncommon. This adverse reaction rarely is severe enough to result in cessation of the drug. In our patient, the most likely cause of the severe myalgias was considered to be adalimumab. The onset and resolution of the signs and symptoms followed a reasonable temporal sequence following drug initiation and discontinuation. In accordance with the data obtained and based on the Naranjo algorithm, the adverse reaction could be considered probable. CONCLUSIONS: This case documents the importance of recognizing the possibility of musculoskeletal adverse reactions even with medications like adalimumab, which have a good safety profile. These findings should further alert clinicians to the potential for myalgias associated with adalimumab administration.

Severe stomatitis complicating treatment with pegylated-interferon alpha-2a and ribavirin in an HCV-infected patient.

OBJECTIVE: To report a case of severe stomatitis probably induced by peginterferon alpha-2a. METHODS AND RESULTS: A 42-year-old man with chronic hepatitis C genotype 1b commenced treatment with peginterferon alpha-2a 180 microg subcutaneously weekly and ribavirin 1000 mg/d orally. Twenty-eight days after commencing treatment, the patient experienced difficulties with swallowing, dryness of the mouth, stomatitis, and pain. Diagnosis of stomatitis was made. He did not complain of any other adverse effect of peginterferon alpha-2a and ribavirin. Both medications were discontinued. The withdrawal of peginterferon alpha-2a was followed by the resolution of the oral lesions in three weeks. The patient was followed up in the outpatient clinic at one month and at three months, and he was asymptomatic. CONCLUSIONS: Manufacturers of peginterferon alpha-2a suggest that mouth ulceration, stomatitis, dysphagia, and glossitis are considered adverse reactions of this medication. In this case, the most likely cause of the stomatitis was considered to be peginterferon alpha-2a because of the close temporal relationship between exposure to the drug and onset of symptoms, as well as the rapid resolution of the symptoms and signs after peginterferon alpha-2a was discontinued. An objective causality assessment revealed that a adverse drug event was possible. Clinicians should be aware of this potentially adverse effect of a widely used drug.

Parapharyngeal abscess in a patient receiving etanercept.

OBJECTIVE: To report a case of parapharyngeal abscess associated with Streptococcus viridans in a patient with rheumatoid arthritis receiving treatment with etanercept. CASE SUMMARY: A 40-year-old man diagnosed with rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, methotrexate, and deflazacort. Six months prior to admission, the patient had a Disease Activity Score of 3.4; clinicians decided to start treatment with etanercept. Chest X-rays were normal and the tuberculin skin test was negative. Treatment with etanercept plus methotrexate was started. Three months later, methotrexate was discontinued. Six months after etanercept therapy was started, the patient presented to our emergency department with a swelling of his neck, odynophagia, otalgia, and trismus. The clinical course was consistent with parapharyngeal abscess. Etanercept treatment was suspended. The parapharyngeal abscess was drained and intravenous methylprednisolone, amoxicillin/clavulanic acid, and clindamycin were administered. The parapharyngeal abscess secretion culture was positive for S. viridans and Bacteroides spp. The patient's condition improved with antibiotic therapy; he was discharged 5 days after admission. DISCUSSION: Tumor necrosis factor-alpha plays an essential role in the immune-mediated response to infection. In our patient, the most possible cause of parapharyngeal abscess was considered to be etanercept because of the temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the abscess developed. Based on the Naranjo probability scale, an association between etanercept and the adverse reaction could be considered possible. CONCLUSIONS: Patients initiated on etanercept therapy should be closely monitored for the development of tuberculosis and other infections. During treatment, all febrile or novel illnesses should be evaluated promptly. If clinical evaluation leads to the suspicion of tuberculosis and other infections associated with etanercept, it should be discontinued immediately.