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Serum urate level governs management of difficult-to-treat gout
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.
“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”
The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.
Addressing intolerance and undertreatment
Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.
“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”
Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.
Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.
Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.
If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.
Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.
Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.
The FAST trial
The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).
“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.
Allopurinol hypersensitivity and chronic kidney disease
Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.
One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.
Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.
Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Take drug, patient-level factors into account for when to end antiresorptive therapy
LAS VEGAS – according to an overview presented by Marcy B. Bolster, MD.
Recently published studies may help guide decisions about initiating and discontinuing treatment with bisphosphonates or denosumab (Prolia), the antiresorptive therapies. Understanding the ideal duration of bisphosphonate drug holidays “is a work in progress,” Dr. Bolster, from Harvard Medical School in Boston, said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
No holiday with denosumab
Data indicate that twice yearly denosumab remains safe at 10 years, but studies have found a rapid loss of bone mineral density and an increased risk for vertebral fractures after treatment is discontinued (J Bone Miner Res. 2018 Feb;33[2]:190-8).
“Therefore, it is not appropriate for denosumab to be utilized with a drug holiday. If a patient is placed on denosumab, then consideration needs to be given for what to follow the course of denosumab,” Dr. Bolster said. “It is important to review with our patients the essential scheduled dosing of every 6 months, that the patient should not miss doses, and that we are not going to be able to initiate a drug holiday without starting another medicine.”
Patients likely to require hospitalization may not be good candidates for denosumab therapy because they may not be able to adhere to the dosing regimen, she said.
Denosumab vs. bisphosphonates: Real-world data
Trials have found greater increases in bone mineral density with denosumab, compared with the bisphosphonate drug alendronate, but that finding does not necessarily equate with reduced fracture risk, Dr. Bolster said. A recent population-based study examined fracture risk in approximately 92,000 people over age 50 years. Most were women, and their mean age was 71 years (JAMA Netw Open. 2019 Apr 5;2[4]:e192416).
The researchers compared the incidence of hospitalization for hip fracture among new denosumab users and new alendronate users during the 3 years after starting treatment. At 3 years, hip fractures occurred in 3.7% of the denosumab group and in 3.1% of the alendronate group. The rate of any fracture was 9% for each group. Although the study design had limitations, the analysis found “no difference between denosumab and alendronate in terms of fracture-risk reduction,” Dr. Bolster said. “Both agents are good agents.”
A recent meta-analysis compared fracture risk with denosumab and any bisphosphonate treatment using data from 10 trials that included more than 5,000 patients (J Clin Endocrinol Metab. 2019 May 1;104[5]:1753-65).
At 12 and 24 months, denosumab produced greater increases in bone mineral density at the spine, hip, and femoral neck. “In fact, there was a greater increase in bone density seen in those on denosumab who had had prior bisphosphonate use,” Dr. Bolster said. In 9 out of 10 trials, however, fracture rate did not differ between patients who received denosumab or any bisphosphonate at 12 or 24 months.
Bisphosphonate drug holidays
An increased risk of atypical femoral fracture with long-term bisphosphonate therapy has driven research on the effects of bisphosphonate drug holidays. “When we start a drug holiday, it requires continued close monitoring of the patient’s risk factors,” as well as monitoring whether a new fracture occurs during the holiday, Dr. Bolster said.
“We have very little data to guide the duration of a drug holiday,” she said. One study examined changes in bone density and bone turnover markers during a drug holiday after treatment with oral alendronate or intravenous zoledronic acid (J Bone Miner Res. 2019 May;34[5]:810-6).
The investigators conducted a post hoc analysis of data from the FLEX and HORIZON trials. Although alendronate was used for a longer duration, compared with zoledronic acid (5 years vs. 3 years), alendronate had a more rapid offset of drug effect after 3 years. The difference may relate to compliance rates with oral therapy during the treatment period, Dr. Bolster said.
The study did not examine fracture rates, which is the outcome that ultimately matters at the end of the day, she said.
Data suggest that bisphosphonate holidays are associated with increased risk of hip fracture. An analysis of Medicare data by Curtis et al. found that “hip fracture rates were lowest among those who remained on bisphosphonates,” Dr. Bolster said. Hip fracture rates increased with the length of the drug holiday, and a drug holiday of between 2 and 3 years was associated with 39% increased risk. The analysis included data from more than 156,000 women, about 40% of whom stopped bisphosphonates for more than 6 months. A total of 3,745 hip fractures occurred during follow-up.
Individualize treatment
“Duration of therapy should be individualized to the patient,” Dr. Bolster said. Physicians should assess the patient’s risk factors and take into account fragility fractures before and during treatment, bone density, and comorbidities.
“In terms of duration for drug holiday, does the patient now have osteopenia after treatment?” she said. “It is uncommon for bone density to change significantly during treatment, but occasionally we have a patient who goes from osteoporosis to osteopenia.”
The resumption of treatment should be based on established guidelines and individual patient factors, she said. For some postmenopausal woman, estrogen or raloxifene may not be ideal treatments when resuming therapy because these medications may increase cardiovascular or thrombotic risks. Denosumab may not be a good option for some patients because of the limitations surrounding its ability to be discontinued. The anabolic agents teriparatide and abaloparatide “may be good options to consider after a drug holiday, or even to give to patients during the drug holiday,” Dr. Bolster said. “The drug holiday does not have to be a treatment holiday. It really just needs to be an antiresorptive holiday.”
Dr. Bolster owns stock in Johnson & Johnson and is on an advisory board for Gilead.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – according to an overview presented by Marcy B. Bolster, MD.
Recently published studies may help guide decisions about initiating and discontinuing treatment with bisphosphonates or denosumab (Prolia), the antiresorptive therapies. Understanding the ideal duration of bisphosphonate drug holidays “is a work in progress,” Dr. Bolster, from Harvard Medical School in Boston, said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
No holiday with denosumab
Data indicate that twice yearly denosumab remains safe at 10 years, but studies have found a rapid loss of bone mineral density and an increased risk for vertebral fractures after treatment is discontinued (J Bone Miner Res. 2018 Feb;33[2]:190-8).
“Therefore, it is not appropriate for denosumab to be utilized with a drug holiday. If a patient is placed on denosumab, then consideration needs to be given for what to follow the course of denosumab,” Dr. Bolster said. “It is important to review with our patients the essential scheduled dosing of every 6 months, that the patient should not miss doses, and that we are not going to be able to initiate a drug holiday without starting another medicine.”
Patients likely to require hospitalization may not be good candidates for denosumab therapy because they may not be able to adhere to the dosing regimen, she said.
Denosumab vs. bisphosphonates: Real-world data
Trials have found greater increases in bone mineral density with denosumab, compared with the bisphosphonate drug alendronate, but that finding does not necessarily equate with reduced fracture risk, Dr. Bolster said. A recent population-based study examined fracture risk in approximately 92,000 people over age 50 years. Most were women, and their mean age was 71 years (JAMA Netw Open. 2019 Apr 5;2[4]:e192416).
The researchers compared the incidence of hospitalization for hip fracture among new denosumab users and new alendronate users during the 3 years after starting treatment. At 3 years, hip fractures occurred in 3.7% of the denosumab group and in 3.1% of the alendronate group. The rate of any fracture was 9% for each group. Although the study design had limitations, the analysis found “no difference between denosumab and alendronate in terms of fracture-risk reduction,” Dr. Bolster said. “Both agents are good agents.”
A recent meta-analysis compared fracture risk with denosumab and any bisphosphonate treatment using data from 10 trials that included more than 5,000 patients (J Clin Endocrinol Metab. 2019 May 1;104[5]:1753-65).
At 12 and 24 months, denosumab produced greater increases in bone mineral density at the spine, hip, and femoral neck. “In fact, there was a greater increase in bone density seen in those on denosumab who had had prior bisphosphonate use,” Dr. Bolster said. In 9 out of 10 trials, however, fracture rate did not differ between patients who received denosumab or any bisphosphonate at 12 or 24 months.
Bisphosphonate drug holidays
An increased risk of atypical femoral fracture with long-term bisphosphonate therapy has driven research on the effects of bisphosphonate drug holidays. “When we start a drug holiday, it requires continued close monitoring of the patient’s risk factors,” as well as monitoring whether a new fracture occurs during the holiday, Dr. Bolster said.
“We have very little data to guide the duration of a drug holiday,” she said. One study examined changes in bone density and bone turnover markers during a drug holiday after treatment with oral alendronate or intravenous zoledronic acid (J Bone Miner Res. 2019 May;34[5]:810-6).
The investigators conducted a post hoc analysis of data from the FLEX and HORIZON trials. Although alendronate was used for a longer duration, compared with zoledronic acid (5 years vs. 3 years), alendronate had a more rapid offset of drug effect after 3 years. The difference may relate to compliance rates with oral therapy during the treatment period, Dr. Bolster said.
The study did not examine fracture rates, which is the outcome that ultimately matters at the end of the day, she said.
Data suggest that bisphosphonate holidays are associated with increased risk of hip fracture. An analysis of Medicare data by Curtis et al. found that “hip fracture rates were lowest among those who remained on bisphosphonates,” Dr. Bolster said. Hip fracture rates increased with the length of the drug holiday, and a drug holiday of between 2 and 3 years was associated with 39% increased risk. The analysis included data from more than 156,000 women, about 40% of whom stopped bisphosphonates for more than 6 months. A total of 3,745 hip fractures occurred during follow-up.
Individualize treatment
“Duration of therapy should be individualized to the patient,” Dr. Bolster said. Physicians should assess the patient’s risk factors and take into account fragility fractures before and during treatment, bone density, and comorbidities.
“In terms of duration for drug holiday, does the patient now have osteopenia after treatment?” she said. “It is uncommon for bone density to change significantly during treatment, but occasionally we have a patient who goes from osteoporosis to osteopenia.”
The resumption of treatment should be based on established guidelines and individual patient factors, she said. For some postmenopausal woman, estrogen or raloxifene may not be ideal treatments when resuming therapy because these medications may increase cardiovascular or thrombotic risks. Denosumab may not be a good option for some patients because of the limitations surrounding its ability to be discontinued. The anabolic agents teriparatide and abaloparatide “may be good options to consider after a drug holiday, or even to give to patients during the drug holiday,” Dr. Bolster said. “The drug holiday does not have to be a treatment holiday. It really just needs to be an antiresorptive holiday.”
Dr. Bolster owns stock in Johnson & Johnson and is on an advisory board for Gilead.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – according to an overview presented by Marcy B. Bolster, MD.
Recently published studies may help guide decisions about initiating and discontinuing treatment with bisphosphonates or denosumab (Prolia), the antiresorptive therapies. Understanding the ideal duration of bisphosphonate drug holidays “is a work in progress,” Dr. Bolster, from Harvard Medical School in Boston, said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
No holiday with denosumab
Data indicate that twice yearly denosumab remains safe at 10 years, but studies have found a rapid loss of bone mineral density and an increased risk for vertebral fractures after treatment is discontinued (J Bone Miner Res. 2018 Feb;33[2]:190-8).
“Therefore, it is not appropriate for denosumab to be utilized with a drug holiday. If a patient is placed on denosumab, then consideration needs to be given for what to follow the course of denosumab,” Dr. Bolster said. “It is important to review with our patients the essential scheduled dosing of every 6 months, that the patient should not miss doses, and that we are not going to be able to initiate a drug holiday without starting another medicine.”
Patients likely to require hospitalization may not be good candidates for denosumab therapy because they may not be able to adhere to the dosing regimen, she said.
Denosumab vs. bisphosphonates: Real-world data
Trials have found greater increases in bone mineral density with denosumab, compared with the bisphosphonate drug alendronate, but that finding does not necessarily equate with reduced fracture risk, Dr. Bolster said. A recent population-based study examined fracture risk in approximately 92,000 people over age 50 years. Most were women, and their mean age was 71 years (JAMA Netw Open. 2019 Apr 5;2[4]:e192416).
The researchers compared the incidence of hospitalization for hip fracture among new denosumab users and new alendronate users during the 3 years after starting treatment. At 3 years, hip fractures occurred in 3.7% of the denosumab group and in 3.1% of the alendronate group. The rate of any fracture was 9% for each group. Although the study design had limitations, the analysis found “no difference between denosumab and alendronate in terms of fracture-risk reduction,” Dr. Bolster said. “Both agents are good agents.”
A recent meta-analysis compared fracture risk with denosumab and any bisphosphonate treatment using data from 10 trials that included more than 5,000 patients (J Clin Endocrinol Metab. 2019 May 1;104[5]:1753-65).
At 12 and 24 months, denosumab produced greater increases in bone mineral density at the spine, hip, and femoral neck. “In fact, there was a greater increase in bone density seen in those on denosumab who had had prior bisphosphonate use,” Dr. Bolster said. In 9 out of 10 trials, however, fracture rate did not differ between patients who received denosumab or any bisphosphonate at 12 or 24 months.
Bisphosphonate drug holidays
An increased risk of atypical femoral fracture with long-term bisphosphonate therapy has driven research on the effects of bisphosphonate drug holidays. “When we start a drug holiday, it requires continued close monitoring of the patient’s risk factors,” as well as monitoring whether a new fracture occurs during the holiday, Dr. Bolster said.
“We have very little data to guide the duration of a drug holiday,” she said. One study examined changes in bone density and bone turnover markers during a drug holiday after treatment with oral alendronate or intravenous zoledronic acid (J Bone Miner Res. 2019 May;34[5]:810-6).
The investigators conducted a post hoc analysis of data from the FLEX and HORIZON trials. Although alendronate was used for a longer duration, compared with zoledronic acid (5 years vs. 3 years), alendronate had a more rapid offset of drug effect after 3 years. The difference may relate to compliance rates with oral therapy during the treatment period, Dr. Bolster said.
The study did not examine fracture rates, which is the outcome that ultimately matters at the end of the day, she said.
Data suggest that bisphosphonate holidays are associated with increased risk of hip fracture. An analysis of Medicare data by Curtis et al. found that “hip fracture rates were lowest among those who remained on bisphosphonates,” Dr. Bolster said. Hip fracture rates increased with the length of the drug holiday, and a drug holiday of between 2 and 3 years was associated with 39% increased risk. The analysis included data from more than 156,000 women, about 40% of whom stopped bisphosphonates for more than 6 months. A total of 3,745 hip fractures occurred during follow-up.
Individualize treatment
“Duration of therapy should be individualized to the patient,” Dr. Bolster said. Physicians should assess the patient’s risk factors and take into account fragility fractures before and during treatment, bone density, and comorbidities.
“In terms of duration for drug holiday, does the patient now have osteopenia after treatment?” she said. “It is uncommon for bone density to change significantly during treatment, but occasionally we have a patient who goes from osteoporosis to osteopenia.”
The resumption of treatment should be based on established guidelines and individual patient factors, she said. For some postmenopausal woman, estrogen or raloxifene may not be ideal treatments when resuming therapy because these medications may increase cardiovascular or thrombotic risks. Denosumab may not be a good option for some patients because of the limitations surrounding its ability to be discontinued. The anabolic agents teriparatide and abaloparatide “may be good options to consider after a drug holiday, or even to give to patients during the drug holiday,” Dr. Bolster said. “The drug holiday does not have to be a treatment holiday. It really just needs to be an antiresorptive holiday.”
Dr. Bolster owns stock in Johnson & Johnson and is on an advisory board for Gilead.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Cannabinoids, stem cells lack evidence for osteoarthritis, expert says
LAS VEGAS – Planned clinical trials may clarify whether they benefit patients, said Joel A. Block, MD, professor of rheumatology at Rush University in Chicago.
Cannabinoid therapy “is on everybody’s mind, including our patients,” Dr. Block said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “Cannabinoid receptors are widely present in all joint tissues, and endocannabinoids are clearly present in OA joint tissue. There is good evidence that the receptors regulate pain responses and central sensitization in a variety of OA animal models.” Where cannabis is legal, many people use it for chronic noncancer pain. Side effects may include altered perception, dizziness, drowsiness, and gastrointestinal adverse events.
Cannabis in the literature
“Nonetheless, if you do a systematic review of all of the randomized clinical trials of cannabinoids in human rheumatic diseases, what you will find is there is a grand total of four,” he said. The trials included patients with rheumatoid arthritis, OA, and fibromyalgia. An analysis of aggregated data found that cannabinoids improved pain and sleep, but all of the trials had a high risk of bias, poor allocation concealment, and poor blinding, said Dr. Block (Arthritis Care Res [Hoboken]. 2016 May;68[5]:681-8.). “In OA, there is one randomized trial, and it was entirely null,” he said. “There was no positive effect on pain or on function in human OA” (Pain. 2012 Sep;153[9]:1837-46.).
ClinicalTrials.gov lists two planned randomized controlled trials of cannabinoids – one using vaporized cannabis in patients with knee OA, and one using cannabidiol for hand OA and psoriatic arthritis. “Clinical trials are still scarce as of right now, so it will take a while before we have evidence for or against,” said Dr. Block.
Stem cell injections
Intra-articular stem cell injections are widely offered in the United States and abroad, he said. “In every newspaper, wherever I go, I open it up and there are full-page ads on stem cell injections that will cure everything that you want,” he said.
A systematic review of the effect of stem cell injections on structural outcomes and pain-related behaviors in animals found that “for all outcomes, the evidence quality was either low or very low,” Dr. Block said (Osteoarthritis Cartilage. 2018 Apr;26[4]:445-61.). “Even in the animal models, it has been very hard to demonstrate any effect at all from just injecting stem cells into the joint.”
Systematic reviews of the evidence in humans have found that the data do not support the use of stem cell injections. The authors of one review concluded, “In the absence of high-level evidence, we do not recommend stem cell therapy” for knee OA (Br J Sports Med. 2017 Aug;51[15]:1125-33.).
For another recent review, researchers screened hundreds of articles and identified 5 trials that met their inclusion criteria. They concluded, “Current evidence does not support the use of intra-articular [mesenchymal stem cells] for improving cartilage repair in knee osteoarthritis” (Arch Orthop Trauma Surg. 2019 Jul;139[7]:971-80.).
Many clinical trials are planned, however. “Over the next several years, I would expect that we are going to get some real data on whether these are helpful or not,” Dr. Block said.
Meanwhile, some patients spend thousands of dollars to receive stem cell injections, and clinics report average patient satisfaction rates of 82%. “How can they be getting so much relief when there is no evidence that it is helpful? In fact, whatever evidence we have says that it is no better than placebo,” said Dr. Block. “Placebo itself is very potent....People always do what they feel helps them regardless of objective data, because placebo itself is very palliative.”
Dr. Block is a consultant for GlaxoSmithKline, Medivir, and Zynerba Pharmaceuticals. He has received royalties from Agios, Daiichi Sankyo, and Omeros. In addition, he has received grant or research support from AbbVie, Janssen, Novartis, Pfizer, and Kolon TissueGene.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Planned clinical trials may clarify whether they benefit patients, said Joel A. Block, MD, professor of rheumatology at Rush University in Chicago.
Cannabinoid therapy “is on everybody’s mind, including our patients,” Dr. Block said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “Cannabinoid receptors are widely present in all joint tissues, and endocannabinoids are clearly present in OA joint tissue. There is good evidence that the receptors regulate pain responses and central sensitization in a variety of OA animal models.” Where cannabis is legal, many people use it for chronic noncancer pain. Side effects may include altered perception, dizziness, drowsiness, and gastrointestinal adverse events.
Cannabis in the literature
“Nonetheless, if you do a systematic review of all of the randomized clinical trials of cannabinoids in human rheumatic diseases, what you will find is there is a grand total of four,” he said. The trials included patients with rheumatoid arthritis, OA, and fibromyalgia. An analysis of aggregated data found that cannabinoids improved pain and sleep, but all of the trials had a high risk of bias, poor allocation concealment, and poor blinding, said Dr. Block (Arthritis Care Res [Hoboken]. 2016 May;68[5]:681-8.). “In OA, there is one randomized trial, and it was entirely null,” he said. “There was no positive effect on pain or on function in human OA” (Pain. 2012 Sep;153[9]:1837-46.).
ClinicalTrials.gov lists two planned randomized controlled trials of cannabinoids – one using vaporized cannabis in patients with knee OA, and one using cannabidiol for hand OA and psoriatic arthritis. “Clinical trials are still scarce as of right now, so it will take a while before we have evidence for or against,” said Dr. Block.
Stem cell injections
Intra-articular stem cell injections are widely offered in the United States and abroad, he said. “In every newspaper, wherever I go, I open it up and there are full-page ads on stem cell injections that will cure everything that you want,” he said.
A systematic review of the effect of stem cell injections on structural outcomes and pain-related behaviors in animals found that “for all outcomes, the evidence quality was either low or very low,” Dr. Block said (Osteoarthritis Cartilage. 2018 Apr;26[4]:445-61.). “Even in the animal models, it has been very hard to demonstrate any effect at all from just injecting stem cells into the joint.”
Systematic reviews of the evidence in humans have found that the data do not support the use of stem cell injections. The authors of one review concluded, “In the absence of high-level evidence, we do not recommend stem cell therapy” for knee OA (Br J Sports Med. 2017 Aug;51[15]:1125-33.).
For another recent review, researchers screened hundreds of articles and identified 5 trials that met their inclusion criteria. They concluded, “Current evidence does not support the use of intra-articular [mesenchymal stem cells] for improving cartilage repair in knee osteoarthritis” (Arch Orthop Trauma Surg. 2019 Jul;139[7]:971-80.).
Many clinical trials are planned, however. “Over the next several years, I would expect that we are going to get some real data on whether these are helpful or not,” Dr. Block said.
Meanwhile, some patients spend thousands of dollars to receive stem cell injections, and clinics report average patient satisfaction rates of 82%. “How can they be getting so much relief when there is no evidence that it is helpful? In fact, whatever evidence we have says that it is no better than placebo,” said Dr. Block. “Placebo itself is very potent....People always do what they feel helps them regardless of objective data, because placebo itself is very palliative.”
Dr. Block is a consultant for GlaxoSmithKline, Medivir, and Zynerba Pharmaceuticals. He has received royalties from Agios, Daiichi Sankyo, and Omeros. In addition, he has received grant or research support from AbbVie, Janssen, Novartis, Pfizer, and Kolon TissueGene.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Planned clinical trials may clarify whether they benefit patients, said Joel A. Block, MD, professor of rheumatology at Rush University in Chicago.
Cannabinoid therapy “is on everybody’s mind, including our patients,” Dr. Block said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “Cannabinoid receptors are widely present in all joint tissues, and endocannabinoids are clearly present in OA joint tissue. There is good evidence that the receptors regulate pain responses and central sensitization in a variety of OA animal models.” Where cannabis is legal, many people use it for chronic noncancer pain. Side effects may include altered perception, dizziness, drowsiness, and gastrointestinal adverse events.
Cannabis in the literature
“Nonetheless, if you do a systematic review of all of the randomized clinical trials of cannabinoids in human rheumatic diseases, what you will find is there is a grand total of four,” he said. The trials included patients with rheumatoid arthritis, OA, and fibromyalgia. An analysis of aggregated data found that cannabinoids improved pain and sleep, but all of the trials had a high risk of bias, poor allocation concealment, and poor blinding, said Dr. Block (Arthritis Care Res [Hoboken]. 2016 May;68[5]:681-8.). “In OA, there is one randomized trial, and it was entirely null,” he said. “There was no positive effect on pain or on function in human OA” (Pain. 2012 Sep;153[9]:1837-46.).
ClinicalTrials.gov lists two planned randomized controlled trials of cannabinoids – one using vaporized cannabis in patients with knee OA, and one using cannabidiol for hand OA and psoriatic arthritis. “Clinical trials are still scarce as of right now, so it will take a while before we have evidence for or against,” said Dr. Block.
Stem cell injections
Intra-articular stem cell injections are widely offered in the United States and abroad, he said. “In every newspaper, wherever I go, I open it up and there are full-page ads on stem cell injections that will cure everything that you want,” he said.
A systematic review of the effect of stem cell injections on structural outcomes and pain-related behaviors in animals found that “for all outcomes, the evidence quality was either low or very low,” Dr. Block said (Osteoarthritis Cartilage. 2018 Apr;26[4]:445-61.). “Even in the animal models, it has been very hard to demonstrate any effect at all from just injecting stem cells into the joint.”
Systematic reviews of the evidence in humans have found that the data do not support the use of stem cell injections. The authors of one review concluded, “In the absence of high-level evidence, we do not recommend stem cell therapy” for knee OA (Br J Sports Med. 2017 Aug;51[15]:1125-33.).
For another recent review, researchers screened hundreds of articles and identified 5 trials that met their inclusion criteria. They concluded, “Current evidence does not support the use of intra-articular [mesenchymal stem cells] for improving cartilage repair in knee osteoarthritis” (Arch Orthop Trauma Surg. 2019 Jul;139[7]:971-80.).
Many clinical trials are planned, however. “Over the next several years, I would expect that we are going to get some real data on whether these are helpful or not,” Dr. Block said.
Meanwhile, some patients spend thousands of dollars to receive stem cell injections, and clinics report average patient satisfaction rates of 82%. “How can they be getting so much relief when there is no evidence that it is helpful? In fact, whatever evidence we have says that it is no better than placebo,” said Dr. Block. “Placebo itself is very potent....People always do what they feel helps them regardless of objective data, because placebo itself is very palliative.”
Dr. Block is a consultant for GlaxoSmithKline, Medivir, and Zynerba Pharmaceuticals. He has received royalties from Agios, Daiichi Sankyo, and Omeros. In addition, he has received grant or research support from AbbVie, Janssen, Novartis, Pfizer, and Kolon TissueGene.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Set reasonable expectations for managing refractory rheumatoid arthritis
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Consider centralized pain in patients with rheumatic disease
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019