Rheumatoid Arthritis

SNOWMASS, COLO. — Long-term adherence to anti–tumor necrosis factor agents appears to be better—and rates of malignancy and serious infection lower—in patients who are treated for ankylosing spondylitis than in those with rheumatoid arthritis or some of the other rheumatic conditions for which the drugs are indicated.

Another major distinction between ankylosing spondylitis (AS) patients and those with other rheumatic diseases in terms of anti-TNF response is that rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients are significantly more likely to remain on treatment long term if they're on concomitant methotrexate, whereas AS patients' unequalled adherence to anti-TNF therapy is not affected by whether or not they're also on methotrexate, Dr. Robert D. Inman said at a symposium sponsored by the American College of Rheumatology.

These observations come from the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) registry. The Norse study also demonstrated that AS patients were an adjusted 34% less likely than those with RA to terminate therapy with infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) during the first year after starting their biologic. The PsA group was 24% less likely than RA patients to discontinue anti-TNF therapy within a year (Arthritis Rheum. 2008;59:234–40).

The reasons cited for discontinuing anti-TNF therapy varied according to disease category. Lack of efficacy was cited as the primary reason by only 18% of PsA patients who quit, compared with 36% of those with AS and 39% of RA patients. Adverse events were cited as the reason for stopping treatment by 69% of PsA patients who discontinued therapy, compared with 44% of those with AS and 49% of RA patients.

The particularly favorable risk:benefit ratio for anti-TNF therapy in AS patients was highlighted in a recent analysis of data on more than 19,000 adalimumab-treated patients in 36 clinical trials that were conducted over a 10-year period. Adalimumab-treated AS patients had rates of malignancy and serious infections as low as or lower than those in patients with the five other immune-mediated inflammatory diseases for which the biologic agent is indicated, said Dr. Inman, professor of medicine and immunology at the University of Toronto.

For example, the rate of tuberculosis and other serious infections was 1.11 per 100 patient-years in AS patients, compared with 4.65 per 100 patient-years in RA patients, 5.18 in those with Crohn's disease, 2.81 in PsA patients, 2.76 in those with juvenile idiopathic arthritis, and 1.32 per 100 patient-years for psoriasis patients.

The incidence of malignancies other than lymphoma and nonmelanoma skin cancer was greatest in the RA population on adalimumab (0.76 cases per 100 patient-years vs. 0.08 per 100 patient-years in the AS group). Patients with RA also had the highest rate of nonmelanoma skin cancer and the second-highest lymphoma rate of the six autoimmune inflammatory diseases for which adalimumab is approved.

As for the relative efficacy of the various anti-TNF drugs in the setting of AS, there is a dearth of head-to-head comparative studies. However, scrutiny of the various placebo-controlled, randomized trials suggests that the efficacy of various agents in AS “looks very comparable,” with 51%–61% of patients on etanercept, infliximab, adalimumab, or golimumab showing a 20% improvement in ASAS 20 (Assessment in Ankylosing Spondylitis 20) at 24 weeks, according to Dr. Inman.

Disclosures: Dr. Inman disclosed serving as a consultant to Sanofi-Aventis, Amgen Inc., Wyeth, Abbott Laboratories, Schering-Plough Corp., and Centocor Inc.

SNOWMASS, COLO. — Long-term adherence to anti–tumor necrosis factor agents appears to be better—and rates of malignancy and serious infection lower—in patients who are treated for ankylosing spondylitis than in those with rheumatoid arthritis or some of the other rheumatic conditions for which the drugs are indicated.

Another major distinction between ankylosing spondylitis (AS) patients and those with other rheumatic diseases in terms of anti-TNF response is that rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients are significantly more likely to remain on treatment long term if they're on concomitant methotrexate, whereas AS patients' unequalled adherence to anti-TNF therapy is not affected by whether or not they're also on methotrexate, Dr. Robert D. Inman said at a symposium sponsored by the American College of Rheumatology.

These observations come from the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) registry. The Norse study also demonstrated that AS patients were an adjusted 34% less likely than those with RA to terminate therapy with infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) during the first year after starting their biologic. The PsA group was 24% less likely than RA patients to discontinue anti-TNF therapy within a year (Arthritis Rheum. 2008;59:234–40).

The reasons cited for discontinuing anti-TNF therapy varied according to disease category. Lack of efficacy was cited as the primary reason by only 18% of PsA patients who quit, compared with 36% of those with AS and 39% of RA patients. Adverse events were cited as the reason for stopping treatment by 69% of PsA patients who discontinued therapy, compared with 44% of those with AS and 49% of RA patients.

The particularly favorable risk:benefit ratio for anti-TNF therapy in AS patients was highlighted in a recent analysis of data on more than 19,000 adalimumab-treated patients in 36 clinical trials that were conducted over a 10-year period. Adalimumab-treated AS patients had rates of malignancy and serious infections as low as or lower than those in patients with the five other immune-mediated inflammatory diseases for which the biologic agent is indicated, said Dr. Inman, professor of medicine and immunology at the University of Toronto.

For example, the rate of tuberculosis and other serious infections was 1.11 per 100 patient-years in AS patients, compared with 4.65 per 100 patient-years in RA patients, 5.18 in those with Crohn's disease, 2.81 in PsA patients, 2.76 in those with juvenile idiopathic arthritis, and 1.32 per 100 patient-years for psoriasis patients.

The incidence of malignancies other than lymphoma and nonmelanoma skin cancer was greatest in the RA population on adalimumab (0.76 cases per 100 patient-years vs. 0.08 per 100 patient-years in the AS group). Patients with RA also had the highest rate of nonmelanoma skin cancer and the second-highest lymphoma rate of the six autoimmune inflammatory diseases for which adalimumab is approved.

As for the relative efficacy of the various anti-TNF drugs in the setting of AS, there is a dearth of head-to-head comparative studies. However, scrutiny of the various placebo-controlled, randomized trials suggests that the efficacy of various agents in AS “looks very comparable,” with 51%–61% of patients on etanercept, infliximab, adalimumab, or golimumab showing a 20% improvement in ASAS 20 (Assessment in Ankylosing Spondylitis 20) at 24 weeks, according to Dr. Inman.

Disclosures: Dr. Inman disclosed serving as a consultant to Sanofi-Aventis, Amgen Inc., Wyeth, Abbott Laboratories, Schering-Plough Corp., and Centocor Inc.

SNOWMASS, COLO. — Long-term adherence to anti–tumor necrosis factor agents appears to be better—and rates of malignancy and serious infection lower—in patients who are treated for ankylosing spondylitis than in those with rheumatoid arthritis or some of the other rheumatic conditions for which the drugs are indicated.

Another major distinction between ankylosing spondylitis (AS) patients and those with other rheumatic diseases in terms of anti-TNF response is that rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients are significantly more likely to remain on treatment long term if they're on concomitant methotrexate, whereas AS patients' unequalled adherence to anti-TNF therapy is not affected by whether or not they're also on methotrexate, Dr. Robert D. Inman said at a symposium sponsored by the American College of Rheumatology.

These observations come from the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) registry. The Norse study also demonstrated that AS patients were an adjusted 34% less likely than those with RA to terminate therapy with infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) during the first year after starting their biologic. The PsA group was 24% less likely than RA patients to discontinue anti-TNF therapy within a year (Arthritis Rheum. 2008;59:234–40).

The reasons cited for discontinuing anti-TNF therapy varied according to disease category. Lack of efficacy was cited as the primary reason by only 18% of PsA patients who quit, compared with 36% of those with AS and 39% of RA patients. Adverse events were cited as the reason for stopping treatment by 69% of PsA patients who discontinued therapy, compared with 44% of those with AS and 49% of RA patients.

The particularly favorable risk:benefit ratio for anti-TNF therapy in AS patients was highlighted in a recent analysis of data on more than 19,000 adalimumab-treated patients in 36 clinical trials that were conducted over a 10-year period. Adalimumab-treated AS patients had rates of malignancy and serious infections as low as or lower than those in patients with the five other immune-mediated inflammatory diseases for which the biologic agent is indicated, said Dr. Inman, professor of medicine and immunology at the University of Toronto.

For example, the rate of tuberculosis and other serious infections was 1.11 per 100 patient-years in AS patients, compared with 4.65 per 100 patient-years in RA patients, 5.18 in those with Crohn's disease, 2.81 in PsA patients, 2.76 in those with juvenile idiopathic arthritis, and 1.32 per 100 patient-years for psoriasis patients.

The incidence of malignancies other than lymphoma and nonmelanoma skin cancer was greatest in the RA population on adalimumab (0.76 cases per 100 patient-years vs. 0.08 per 100 patient-years in the AS group). Patients with RA also had the highest rate of nonmelanoma skin cancer and the second-highest lymphoma rate of the six autoimmune inflammatory diseases for which adalimumab is approved.

As for the relative efficacy of the various anti-TNF drugs in the setting of AS, there is a dearth of head-to-head comparative studies. However, scrutiny of the various placebo-controlled, randomized trials suggests that the efficacy of various agents in AS “looks very comparable,” with 51%–61% of patients on etanercept, infliximab, adalimumab, or golimumab showing a 20% improvement in ASAS 20 (Assessment in Ankylosing Spondylitis 20) at 24 weeks, according to Dr. Inman.

Disclosures: Dr. Inman disclosed serving as a consultant to Sanofi-Aventis, Amgen Inc., Wyeth, Abbott Laboratories, Schering-Plough Corp., and Centocor Inc.

Major Finding: Among older patients treated topically for knee osteoarthritis for 12 weeks, adverse events occurred in 56% of those using diclofenac sodium 1% gel and in 44% of those using placebo, with one serious adverse event possibly related to treatment.

Data Source: A post hoc analysis of data on 538 patients aged 65 years or older from three double-blind, randomized, controlled trials.

Disclosures: Dr. Barthel conducted the study under a research contract for Novartis, which makes the gel. His associates in the study were employees of Novartis or of Endo Pharmaceuticals, which markets the gel.

LONG BEACH, CALIF. — A higher rate of adverse events in older patients with knee osteoarthritis treated topically for 12 weeks with a nonsteroidal anti-inflammatory drug, compared with placebo, was caused mainly by application-site reactions but included one serious cardiovascular event that might have been related to the drug treatment, a post hoc analysis of data on 538 patients found.

The investigators analyzed data on people aged 65 years and older with symptomatic knee osteoarthritis (433 of them with comorbid hypertension, diabetes, or cardiovascular disease). Their source was three larger randomized, double-blind trials—two of them unpublished—that had looked at broader populations. Patients applied 4 g/day of either diclofenac sodium 1% gel (Voltaren) or the drug's vehicle to one painful knee.

One 80-year-old woman with hypertension and diabetes, among 274 patients on diclofenac sodium 1% gel, developed deep vein thrombosis and pulmonary embolism that possibly was related to treatment, Dr. H. Richard Barthel and associates reported in a poster presentation at the annual meeting of the American Medical Directors Association.

Overall, 56% of patients on diclofenac gel developed adverse events, compared with 44% of 264 patients treated with placebo, added Dr. Barthel, a rheumatologist in Santa Barbara, Calif., who conducts research under contract for Voltaren maker, Novartis.

The study was not powered to assess statistical significance. Voltaren is approved to treat osteoarthritis pain in joints amenable to topical treatment, such as knees and hands.

NSAIDs are known to increase risk for cardiovascular or renal problems in a dose-related fashion, especially in older patients and people with hypertension, diabetes, or cardiovascular disease. Topical formulations may reduce this risk by reducing systemic exposure to NSAIDs compared with oral formulations. The ad hoc analysis compared the gel only to placebo, not to oral therapy, and found higher rates of adverse events for the drug vs. placebo.

Application-site reactions occurred in 8.8% on diclofenac gel and 1.1% on placebo. Serious adverse events occurred in 2.6% on diclofenac and 1.1% on placebo. Adverse cardiovascular events were seen in 2.6% on diclofenac and 1.1% on placebo. Adverse renal events were seen in 1.1% on diclofenac and 0.4% on placebo.

Among more common adverse events, 11% of subjects on diclofenac and 10% on placebo reported headache, 8% on diclofenac and 7% on placebo reported arthralgia, and 8% on diclofenac and 6% on placebo reported back pain.

The analysis included 307 patients with hypertension, 84 with diabetes, and 42 with cardiovascular disease. The investigators looked at rates of adverse events in patients with one of these comorbidities, compared with events in patients without the comorbidity. For example, in the hypertension subgroup, adverse events were seen in 54% of 159 people randomized to diclofenac gel, compared with 45% of 148 people using placebo. In patients without hypertension, adverse events occurred in 58% of 115 on diclofenac gel and 42% of 116 on placebo.

In the diabetes subgroup, adverse events occurred in 19 (51%) of 37 patients treated with diclofenac and in 21 (48%) of 47 treated with placebo. In patients without diabetes, adverse events occurred in 56% of 237 on diclofenac and in 44% of 217 on placebo.

In the subgroup with cardiovascular disease, adverse events occurred in 15 (56%) of 27 people on diclofenac and in 2 (13%) of 15 on placebo, although none developed an adverse cardiovascular event.

My Take

Topical Diclofenac Can Fill a Tx Gap

The therapy of osteoarthritis remains insufficient in many patients. It is particularly problematic in the elderly who often have concomitant diseases that limit our options for several of the oral medications, particularly NSAIDs and potent analgesics. The recent Food and Drug Administration approval of diclofenac has changed the therapeutic paradigm. Diclofenac gel 1% has been approved for osteoarthritis of the knee, hand, and other superficial joints, and Pennsaid has been approved for osteoarthritis of the knee.

In this post hoc pooled analysis of 538 patients, we see an increase in irritation at the site of application, but a minimal increase in adverse events involving blood pressure, renal function, hepatic dysfunction, and gastrointestinal ulcer disease. Pharmacokinetic studies have demonstrated that systemic absorption of the topical diclofenac is 40 times less than oral diclofenac. This improved safety allows us to provide therapy to patients otherwise unable to receive anti-inflammatory drugs. It will be no surprise if the guidelines for therapy of osteoarthritis from the United States will soon approximate those from Europe, where topical NSAIDs are part of the therapeutic algorithm for osteoarthritis. Are they completely safe? No. Is there no long-term cardiovascular risk? It has not been studied. Hence, the “black box” warning is applied to these agents that primarily list topical changes under adverse events.

ROY D. ALTMAN, M.D., is professor of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He has been a consultant to Novartis, Eli Lilly, Ferring Pharmaceuticals, and Rottapharm/Madaus.

Vitals

Major Finding: Among older patients treated topically for knee osteoarthritis for 12 weeks, adverse events occurred in 56% of those using diclofenac sodium 1% gel and in 44% of those using placebo, with one serious adverse event possibly related to treatment.

Data Source: A post hoc analysis of data on 538 patients aged 65 years or older from three double-blind, randomized, controlled trials.

Disclosures: Dr. Barthel conducted the study under a research contract for Novartis, which makes the gel. His associates in the study were employees of Novartis or of Endo Pharmaceuticals, which markets the gel.

LONG BEACH, CALIF. — A higher rate of adverse events in older patients with knee osteoarthritis treated topically for 12 weeks with a nonsteroidal anti-inflammatory drug, compared with placebo, was caused mainly by application-site reactions but included one serious cardiovascular event that might have been related to the drug treatment, a post hoc analysis of data on 538 patients found.

The investigators analyzed data on people aged 65 years and older with symptomatic knee osteoarthritis (433 of them with comorbid hypertension, diabetes, or cardiovascular disease). Their source was three larger randomized, double-blind trials—two of them unpublished—that had looked at broader populations. Patients applied 4 g/day of either diclofenac sodium 1% gel (Voltaren) or the drug's vehicle to one painful knee.

One 80-year-old woman with hypertension and diabetes, among 274 patients on diclofenac sodium 1% gel, developed deep vein thrombosis and pulmonary embolism that possibly was related to treatment, Dr. H. Richard Barthel and associates reported in a poster presentation at the annual meeting of the American Medical Directors Association.

Overall, 56% of patients on diclofenac gel developed adverse events, compared with 44% of 264 patients treated with placebo, added Dr. Barthel, a rheumatologist in Santa Barbara, Calif., who conducts research under contract for Voltaren maker, Novartis.

The study was not powered to assess statistical significance. Voltaren is approved to treat osteoarthritis pain in joints amenable to topical treatment, such as knees and hands.

NSAIDs are known to increase risk for cardiovascular or renal problems in a dose-related fashion, especially in older patients and people with hypertension, diabetes, or cardiovascular disease. Topical formulations may reduce this risk by reducing systemic exposure to NSAIDs compared with oral formulations. The ad hoc analysis compared the gel only to placebo, not to oral therapy, and found higher rates of adverse events for the drug vs. placebo.

Application-site reactions occurred in 8.8% on diclofenac gel and 1.1% on placebo. Serious adverse events occurred in 2.6% on diclofenac and 1.1% on placebo. Adverse cardiovascular events were seen in 2.6% on diclofenac and 1.1% on placebo. Adverse renal events were seen in 1.1% on diclofenac and 0.4% on placebo.

Among more common adverse events, 11% of subjects on diclofenac and 10% on placebo reported headache, 8% on diclofenac and 7% on placebo reported arthralgia, and 8% on diclofenac and 6% on placebo reported back pain.

The analysis included 307 patients with hypertension, 84 with diabetes, and 42 with cardiovascular disease. The investigators looked at rates of adverse events in patients with one of these comorbidities, compared with events in patients without the comorbidity. For example, in the hypertension subgroup, adverse events were seen in 54% of 159 people randomized to diclofenac gel, compared with 45% of 148 people using placebo. In patients without hypertension, adverse events occurred in 58% of 115 on diclofenac gel and 42% of 116 on placebo.

In the diabetes subgroup, adverse events occurred in 19 (51%) of 37 patients treated with diclofenac and in 21 (48%) of 47 treated with placebo. In patients without diabetes, adverse events occurred in 56% of 237 on diclofenac and in 44% of 217 on placebo.

In the subgroup with cardiovascular disease, adverse events occurred in 15 (56%) of 27 people on diclofenac and in 2 (13%) of 15 on placebo, although none developed an adverse cardiovascular event.

My Take

Topical Diclofenac Can Fill a Tx Gap

The therapy of osteoarthritis remains insufficient in many patients. It is particularly problematic in the elderly who often have concomitant diseases that limit our options for several of the oral medications, particularly NSAIDs and potent analgesics. The recent Food and Drug Administration approval of diclofenac has changed the therapeutic paradigm. Diclofenac gel 1% has been approved for osteoarthritis of the knee, hand, and other superficial joints, and Pennsaid has been approved for osteoarthritis of the knee.

In this post hoc pooled analysis of 538 patients, we see an increase in irritation at the site of application, but a minimal increase in adverse events involving blood pressure, renal function, hepatic dysfunction, and gastrointestinal ulcer disease. Pharmacokinetic studies have demonstrated that systemic absorption of the topical diclofenac is 40 times less than oral diclofenac. This improved safety allows us to provide therapy to patients otherwise unable to receive anti-inflammatory drugs. It will be no surprise if the guidelines for therapy of osteoarthritis from the United States will soon approximate those from Europe, where topical NSAIDs are part of the therapeutic algorithm for osteoarthritis. Are they completely safe? No. Is there no long-term cardiovascular risk? It has not been studied. Hence, the “black box” warning is applied to these agents that primarily list topical changes under adverse events.

ROY D. ALTMAN, M.D., is professor of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He has been a consultant to Novartis, Eli Lilly, Ferring Pharmaceuticals, and Rottapharm/Madaus.

Vitals

Major Finding: Among older patients treated topically for knee osteoarthritis for 12 weeks, adverse events occurred in 56% of those using diclofenac sodium 1% gel and in 44% of those using placebo, with one serious adverse event possibly related to treatment.

Data Source: A post hoc analysis of data on 538 patients aged 65 years or older from three double-blind, randomized, controlled trials.

Disclosures: Dr. Barthel conducted the study under a research contract for Novartis, which makes the gel. His associates in the study were employees of Novartis or of Endo Pharmaceuticals, which markets the gel.

LONG BEACH, CALIF. — A higher rate of adverse events in older patients with knee osteoarthritis treated topically for 12 weeks with a nonsteroidal anti-inflammatory drug, compared with placebo, was caused mainly by application-site reactions but included one serious cardiovascular event that might have been related to the drug treatment, a post hoc analysis of data on 538 patients found.

The investigators analyzed data on people aged 65 years and older with symptomatic knee osteoarthritis (433 of them with comorbid hypertension, diabetes, or cardiovascular disease). Their source was three larger randomized, double-blind trials—two of them unpublished—that had looked at broader populations. Patients applied 4 g/day of either diclofenac sodium 1% gel (Voltaren) or the drug's vehicle to one painful knee.

One 80-year-old woman with hypertension and diabetes, among 274 patients on diclofenac sodium 1% gel, developed deep vein thrombosis and pulmonary embolism that possibly was related to treatment, Dr. H. Richard Barthel and associates reported in a poster presentation at the annual meeting of the American Medical Directors Association.

Overall, 56% of patients on diclofenac gel developed adverse events, compared with 44% of 264 patients treated with placebo, added Dr. Barthel, a rheumatologist in Santa Barbara, Calif., who conducts research under contract for Voltaren maker, Novartis.

The study was not powered to assess statistical significance. Voltaren is approved to treat osteoarthritis pain in joints amenable to topical treatment, such as knees and hands.

NSAIDs are known to increase risk for cardiovascular or renal problems in a dose-related fashion, especially in older patients and people with hypertension, diabetes, or cardiovascular disease. Topical formulations may reduce this risk by reducing systemic exposure to NSAIDs compared with oral formulations. The ad hoc analysis compared the gel only to placebo, not to oral therapy, and found higher rates of adverse events for the drug vs. placebo.

Application-site reactions occurred in 8.8% on diclofenac gel and 1.1% on placebo. Serious adverse events occurred in 2.6% on diclofenac and 1.1% on placebo. Adverse cardiovascular events were seen in 2.6% on diclofenac and 1.1% on placebo. Adverse renal events were seen in 1.1% on diclofenac and 0.4% on placebo.

Among more common adverse events, 11% of subjects on diclofenac and 10% on placebo reported headache, 8% on diclofenac and 7% on placebo reported arthralgia, and 8% on diclofenac and 6% on placebo reported back pain.

The analysis included 307 patients with hypertension, 84 with diabetes, and 42 with cardiovascular disease. The investigators looked at rates of adverse events in patients with one of these comorbidities, compared with events in patients without the comorbidity. For example, in the hypertension subgroup, adverse events were seen in 54% of 159 people randomized to diclofenac gel, compared with 45% of 148 people using placebo. In patients without hypertension, adverse events occurred in 58% of 115 on diclofenac gel and 42% of 116 on placebo.

In the diabetes subgroup, adverse events occurred in 19 (51%) of 37 patients treated with diclofenac and in 21 (48%) of 47 treated with placebo. In patients without diabetes, adverse events occurred in 56% of 237 on diclofenac and in 44% of 217 on placebo.

In the subgroup with cardiovascular disease, adverse events occurred in 15 (56%) of 27 people on diclofenac and in 2 (13%) of 15 on placebo, although none developed an adverse cardiovascular event.

My Take

Topical Diclofenac Can Fill a Tx Gap

The therapy of osteoarthritis remains insufficient in many patients. It is particularly problematic in the elderly who often have concomitant diseases that limit our options for several of the oral medications, particularly NSAIDs and potent analgesics. The recent Food and Drug Administration approval of diclofenac has changed the therapeutic paradigm. Diclofenac gel 1% has been approved for osteoarthritis of the knee, hand, and other superficial joints, and Pennsaid has been approved for osteoarthritis of the knee.

In this post hoc pooled analysis of 538 patients, we see an increase in irritation at the site of application, but a minimal increase in adverse events involving blood pressure, renal function, hepatic dysfunction, and gastrointestinal ulcer disease. Pharmacokinetic studies have demonstrated that systemic absorption of the topical diclofenac is 40 times less than oral diclofenac. This improved safety allows us to provide therapy to patients otherwise unable to receive anti-inflammatory drugs. It will be no surprise if the guidelines for therapy of osteoarthritis from the United States will soon approximate those from Europe, where topical NSAIDs are part of the therapeutic algorithm for osteoarthritis. Are they completely safe? No. Is there no long-term cardiovascular risk? It has not been studied. Hence, the “black box” warning is applied to these agents that primarily list topical changes under adverse events.

ROY D. ALTMAN, M.D., is professor of medicine in the division of rheumatology and immunology at the University of California, Los Angeles. He has been a consultant to Novartis, Eli Lilly, Ferring Pharmaceuticals, and Rottapharm/Madaus.

Vitals

NEW YORK — New evidence that children with the systemic form of juvenile idiopathic arthritis respond better to treatment with anakinra than do those with other types of arthritis lends credence to the hypothesis that a different pathway underlies systemic disease, according to Dr. Norman T. Ilowite.

In an open-label study, the response rate was 73% (11 of 15) for children with systemic juvenile idiopathic arthritis (JIA), compared with 67% (6 of 9) for children with pauciarticular and 52% (29 of 56) for children with polyarticular JIA.

The overall response rate was 58% (46 of 80), according to Dr. Ilowite, who reported his findings at a rheumatology meeting sponsored by New York University.

“These observations are in contradistinction to those seen in most studies of [tumor necrosis factor] therapies in JIA, where those with systemic disease didn't do as well as those with polyarticular or oligoarticular disease,” said Dr. Ilowite, chief of pediatric rheumatology at Children's Hospital at Montefiore Medical Center and professor of pediatrics at the Albert Einstein College of Medicine, both in New York.

Anakinra is similar to a naturally occurring interleukin-1 (IL-1) receptor antagonist that has been approved for the management of signs and symptoms of rheumatoid arthritis in adults. It has not received approval for use in children with arthritis.

It has been proposed that inflammation in systemic JIA is mediated by IL-1, and thus that the inhibition of IL-1's proinflammatory effects would be an attractive therapeutic strategy.

Systemic JIA appears to be similar to other autoinflammatory syndromes in which IL-1 inhibition has been used successfully as therapy, including neonatal-onset multisystem inflammatory disease (NOMID) and cryopyrin-associated periodic syndromes (CAPS), said Dr. Ilowite.

Although the number of patients enrolled was small, Dr. Ilowite also presented data suggesting that anakinra was safe and reduced the number of disease flares across all subtypes of JIA, compared with placebo (Clin. Rheumatol. 2009;28:129–37).

Systemic JIA affects about 10% of children who have JIA, said Dr. Ilowite. It is the only subtype that causes fever, and arthritis usually ensues within 6 months of fever onset. It begins with mostly extra-articular manifestations, and is the only subtype with no strong HLA, sex, or age predilections.

The course is highly variable, with about 40% following a uniphasic course that fades within about 2 years, about 55% following a persistent course that progresses rapidly with serious systemic manifestations, and about 5% having intermittent exacerbations and remissions. Extra-articular manifestations include daily fever with two spikes a day, hepatosplenomegaly, lymphadenopathy, and rash.

Macrophage activation syndrome, a potentially fatal complication, occurs in about 7% of children with systemic JIA, according to Dr. Ilowite.

Other studies also suggest a preferential importance of IL-1 pathway activation in systemic JIA.

Anakinra was effective in a retrospective study of 33 patients with systemic JIA (J. Clin. Rheumatol. 2009;15:161–4). Furthermore, a characteristic IL-1 signature was reversed among systemic JIA patients who were treated with anakinra (J. Exp. Med. 2005;201:1479–86).

Disclosures: Dr. Ilowite had nothing to disclose. His study is reporting on unapproved indications for anakinra.

NEW YORK — New evidence that children with the systemic form of juvenile idiopathic arthritis respond better to treatment with anakinra than do those with other types of arthritis lends credence to the hypothesis that a different pathway underlies systemic disease, according to Dr. Norman T. Ilowite.

In an open-label study, the response rate was 73% (11 of 15) for children with systemic juvenile idiopathic arthritis (JIA), compared with 67% (6 of 9) for children with pauciarticular and 52% (29 of 56) for children with polyarticular JIA.

The overall response rate was 58% (46 of 80), according to Dr. Ilowite, who reported his findings at a rheumatology meeting sponsored by New York University.

“These observations are in contradistinction to those seen in most studies of [tumor necrosis factor] therapies in JIA, where those with systemic disease didn't do as well as those with polyarticular or oligoarticular disease,” said Dr. Ilowite, chief of pediatric rheumatology at Children's Hospital at Montefiore Medical Center and professor of pediatrics at the Albert Einstein College of Medicine, both in New York.

Anakinra is similar to a naturally occurring interleukin-1 (IL-1) receptor antagonist that has been approved for the management of signs and symptoms of rheumatoid arthritis in adults. It has not received approval for use in children with arthritis.

It has been proposed that inflammation in systemic JIA is mediated by IL-1, and thus that the inhibition of IL-1's proinflammatory effects would be an attractive therapeutic strategy.

Systemic JIA appears to be similar to other autoinflammatory syndromes in which IL-1 inhibition has been used successfully as therapy, including neonatal-onset multisystem inflammatory disease (NOMID) and cryopyrin-associated periodic syndromes (CAPS), said Dr. Ilowite.

Although the number of patients enrolled was small, Dr. Ilowite also presented data suggesting that anakinra was safe and reduced the number of disease flares across all subtypes of JIA, compared with placebo (Clin. Rheumatol. 2009;28:129–37).

Systemic JIA affects about 10% of children who have JIA, said Dr. Ilowite. It is the only subtype that causes fever, and arthritis usually ensues within 6 months of fever onset. It begins with mostly extra-articular manifestations, and is the only subtype with no strong HLA, sex, or age predilections.

The course is highly variable, with about 40% following a uniphasic course that fades within about 2 years, about 55% following a persistent course that progresses rapidly with serious systemic manifestations, and about 5% having intermittent exacerbations and remissions. Extra-articular manifestations include daily fever with two spikes a day, hepatosplenomegaly, lymphadenopathy, and rash.

Macrophage activation syndrome, a potentially fatal complication, occurs in about 7% of children with systemic JIA, according to Dr. Ilowite.

Other studies also suggest a preferential importance of IL-1 pathway activation in systemic JIA.

Anakinra was effective in a retrospective study of 33 patients with systemic JIA (J. Clin. Rheumatol. 2009;15:161–4). Furthermore, a characteristic IL-1 signature was reversed among systemic JIA patients who were treated with anakinra (J. Exp. Med. 2005;201:1479–86).

Disclosures: Dr. Ilowite had nothing to disclose. His study is reporting on unapproved indications for anakinra.

NEW YORK — New evidence that children with the systemic form of juvenile idiopathic arthritis respond better to treatment with anakinra than do those with other types of arthritis lends credence to the hypothesis that a different pathway underlies systemic disease, according to Dr. Norman T. Ilowite.

In an open-label study, the response rate was 73% (11 of 15) for children with systemic juvenile idiopathic arthritis (JIA), compared with 67% (6 of 9) for children with pauciarticular and 52% (29 of 56) for children with polyarticular JIA.

The overall response rate was 58% (46 of 80), according to Dr. Ilowite, who reported his findings at a rheumatology meeting sponsored by New York University.

“These observations are in contradistinction to those seen in most studies of [tumor necrosis factor] therapies in JIA, where those with systemic disease didn't do as well as those with polyarticular or oligoarticular disease,” said Dr. Ilowite, chief of pediatric rheumatology at Children's Hospital at Montefiore Medical Center and professor of pediatrics at the Albert Einstein College of Medicine, both in New York.

Anakinra is similar to a naturally occurring interleukin-1 (IL-1) receptor antagonist that has been approved for the management of signs and symptoms of rheumatoid arthritis in adults. It has not received approval for use in children with arthritis.

It has been proposed that inflammation in systemic JIA is mediated by IL-1, and thus that the inhibition of IL-1's proinflammatory effects would be an attractive therapeutic strategy.

Systemic JIA appears to be similar to other autoinflammatory syndromes in which IL-1 inhibition has been used successfully as therapy, including neonatal-onset multisystem inflammatory disease (NOMID) and cryopyrin-associated periodic syndromes (CAPS), said Dr. Ilowite.

Although the number of patients enrolled was small, Dr. Ilowite also presented data suggesting that anakinra was safe and reduced the number of disease flares across all subtypes of JIA, compared with placebo (Clin. Rheumatol. 2009;28:129–37).

Systemic JIA affects about 10% of children who have JIA, said Dr. Ilowite. It is the only subtype that causes fever, and arthritis usually ensues within 6 months of fever onset. It begins with mostly extra-articular manifestations, and is the only subtype with no strong HLA, sex, or age predilections.

The course is highly variable, with about 40% following a uniphasic course that fades within about 2 years, about 55% following a persistent course that progresses rapidly with serious systemic manifestations, and about 5% having intermittent exacerbations and remissions. Extra-articular manifestations include daily fever with two spikes a day, hepatosplenomegaly, lymphadenopathy, and rash.

Macrophage activation syndrome, a potentially fatal complication, occurs in about 7% of children with systemic JIA, according to Dr. Ilowite.

Other studies also suggest a preferential importance of IL-1 pathway activation in systemic JIA.

Anakinra was effective in a retrospective study of 33 patients with systemic JIA (J. Clin. Rheumatol. 2009;15:161–4). Furthermore, a characteristic IL-1 signature was reversed among systemic JIA patients who were treated with anakinra (J. Exp. Med. 2005;201:1479–86).

Disclosures: Dr. Ilowite had nothing to disclose. His study is reporting on unapproved indications for anakinra.

SNOWMASS, COLO. — A wide range of rheumatic diseases is associated with increased risk for myeloid malignancies, according to an analysis of the National Cancer Institute's Surveillance, Epidemiology and End Results database.

Epidemiologic studies such as this SEER analysis can't address causation. But it's clear that much of the increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and other rheumatic diseases is a consequence of the medications used in treating the autoimmune disease, Dr. Maria R. Baer said at a symposium sponsored by the American College of Rheumatology.

Shared genetic predisposition and extension of the rheumatic disease into the bone marrow are other possible explanations.

There is a well-established association between rheumatic conditions and an increased risk of lymphoma. The risk of myeloid malignancies in rheumatology patients has, until recently, undergone far less scrutiny, noted Dr. Baer, a hematologist and oncologist at the cancer center of the University of Maryland in Baltimore.

The retrospective, case-control SEER study, conducted by investigators at Queen's University of Belfast (Northern Ireland), incorporated 13,486 U.S. patients with myeloid malignancies and 160,086 controls.

Multiple logistic regression analyses, adjusted for potential confounders, showed that rheumatic diseases were associated with an overall 1.29-fold increased risk of AML. The AML risk varied by the specific rheumatologic disease. It was greatest in systemic vasculitis patients, who were at 6.23-fold greater risk than were controls who were free of rheumatic diseases.

On the other hand, systemic vasculitis was the only rheumatic disease included in the study that was not associated with an elevated risk of MDS. (See box.)

The autoimmune diseases weren't associated with overall increased risks of chronic myeloid leukemia or chronic myeloproliferative disorders (Br. J. Cancer 2009;100:822–8).

Another informative, large, retrospective cohort study was conducted by investigators at the California Cancer Registry. They found that in 30,478 patients with SLE who were followed for nearly 158,000 person-years, the risk of myeloid leukemia was increased 2.96-fold. The SLE patients also had a 2.7-fold increased risk of liver cancer, a 3.27-fold increased of vaginal/vulvar cancer, and elevated risks of lung, thyroid, and renal cancers (Cancer Causes Control 2008;19:887–94).

The same team of investigators subsequently studied 84,475 rheumatoid arthritis patients over an observation period stretching in excess of 405,000 person-years. The patients proved to have significantly increased risks of hematopoietic, lung, liver, and esophageal cancers. They also had lower-than-average rates of several screenable cancers, as did the SLE patients in the earlier study (Cancer Causes Control 2009;20:1001–10).

Cytotoxic therapy–related MDS and AML (abbreviated by hematologists as t-MDS and t-AML) have a readily identifiable pathological pattern. It is characterized by morphological dysplasia of the bone marrow and clonal cytogenetic abnormalities, most often loss of part or all of chromosome 5 or 7 or both. Although t-MDS often evolves into t-AML, t-AML isn't always preceded by t-MDS. The distinction between the two, as arbitrarily defined by the World Health Organization, is that t-AML features at least 20% myeloblasts, Dr. Baer continued.

Methotrexate use doesn't appear to be linked to the increased risk of t-MDS or t-AML, although it is associated with an increased risk of lymphoma.

In contrast, cyclophosphamide is a major culprit in the t-MDS and t-AML that are encountered in rheumatology patients. In what Dr. Baer termed “a classic” study, Danish investigators showed that in a cohort of 293 patients with Wegener's granulomatosis who were followed for 2,121 person-years, the risk of AML was increased 19.6-fold overall, compared with that of the general population. The risk was not elevated above that in controls for Wegener's patients who had received a cumulative 36 g or less of cyclophosphamide. However, patients who had received more than 36 g (equivalent to 100 mg/day for more than a year) had a 59-fold increased risk of AML (J. Rheumatol. 2008;35:100–5).

Both t-MDS and t-AML are “bad entities,” she emphasized. The first question to ask is whether an affected patient is a candidate for aggressive therapy with allogeneic hematopoietic stem cell transplantation—the clear treatment of choice—and if so, whether a donor is available.

“The outcome is really dismal, transplant or no transplant. You want to modulate your rheumatologic therapy to avoid this complication because it's quite devastating when it does occur,” Dr. Baer said.

She offered as one representative series a 306-patient University of Chicago cohort. Their median survival after diagnosis of t-MDS or t-AML was 8 months, with a 5-year survival of less than 10% (Blood 2003;102:43–52).

Disclosures: Dr. Baer reported no relevant financial relationships.

Source Elsevier Global Medical News

SNOWMASS, COLO. — A wide range of rheumatic diseases is associated with increased risk for myeloid malignancies, according to an analysis of the National Cancer Institute's Surveillance, Epidemiology and End Results database.

Epidemiologic studies such as this SEER analysis can't address causation. But it's clear that much of the increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and other rheumatic diseases is a consequence of the medications used in treating the autoimmune disease, Dr. Maria R. Baer said at a symposium sponsored by the American College of Rheumatology.

Shared genetic predisposition and extension of the rheumatic disease into the bone marrow are other possible explanations.

There is a well-established association between rheumatic conditions and an increased risk of lymphoma. The risk of myeloid malignancies in rheumatology patients has, until recently, undergone far less scrutiny, noted Dr. Baer, a hematologist and oncologist at the cancer center of the University of Maryland in Baltimore.

The retrospective, case-control SEER study, conducted by investigators at Queen's University of Belfast (Northern Ireland), incorporated 13,486 U.S. patients with myeloid malignancies and 160,086 controls.

Multiple logistic regression analyses, adjusted for potential confounders, showed that rheumatic diseases were associated with an overall 1.29-fold increased risk of AML. The AML risk varied by the specific rheumatologic disease. It was greatest in systemic vasculitis patients, who were at 6.23-fold greater risk than were controls who were free of rheumatic diseases.

On the other hand, systemic vasculitis was the only rheumatic disease included in the study that was not associated with an elevated risk of MDS. (See box.)

The autoimmune diseases weren't associated with overall increased risks of chronic myeloid leukemia or chronic myeloproliferative disorders (Br. J. Cancer 2009;100:822–8).

Another informative, large, retrospective cohort study was conducted by investigators at the California Cancer Registry. They found that in 30,478 patients with SLE who were followed for nearly 158,000 person-years, the risk of myeloid leukemia was increased 2.96-fold. The SLE patients also had a 2.7-fold increased risk of liver cancer, a 3.27-fold increased of vaginal/vulvar cancer, and elevated risks of lung, thyroid, and renal cancers (Cancer Causes Control 2008;19:887–94).

The same team of investigators subsequently studied 84,475 rheumatoid arthritis patients over an observation period stretching in excess of 405,000 person-years. The patients proved to have significantly increased risks of hematopoietic, lung, liver, and esophageal cancers. They also had lower-than-average rates of several screenable cancers, as did the SLE patients in the earlier study (Cancer Causes Control 2009;20:1001–10).

Cytotoxic therapy–related MDS and AML (abbreviated by hematologists as t-MDS and t-AML) have a readily identifiable pathological pattern. It is characterized by morphological dysplasia of the bone marrow and clonal cytogenetic abnormalities, most often loss of part or all of chromosome 5 or 7 or both. Although t-MDS often evolves into t-AML, t-AML isn't always preceded by t-MDS. The distinction between the two, as arbitrarily defined by the World Health Organization, is that t-AML features at least 20% myeloblasts, Dr. Baer continued.

Methotrexate use doesn't appear to be linked to the increased risk of t-MDS or t-AML, although it is associated with an increased risk of lymphoma.

In contrast, cyclophosphamide is a major culprit in the t-MDS and t-AML that are encountered in rheumatology patients. In what Dr. Baer termed “a classic” study, Danish investigators showed that in a cohort of 293 patients with Wegener's granulomatosis who were followed for 2,121 person-years, the risk of AML was increased 19.6-fold overall, compared with that of the general population. The risk was not elevated above that in controls for Wegener's patients who had received a cumulative 36 g or less of cyclophosphamide. However, patients who had received more than 36 g (equivalent to 100 mg/day for more than a year) had a 59-fold increased risk of AML (J. Rheumatol. 2008;35:100–5).

Both t-MDS and t-AML are “bad entities,” she emphasized. The first question to ask is whether an affected patient is a candidate for aggressive therapy with allogeneic hematopoietic stem cell transplantation—the clear treatment of choice—and if so, whether a donor is available.

“The outcome is really dismal, transplant or no transplant. You want to modulate your rheumatologic therapy to avoid this complication because it's quite devastating when it does occur,” Dr. Baer said.

She offered as one representative series a 306-patient University of Chicago cohort. Their median survival after diagnosis of t-MDS or t-AML was 8 months, with a 5-year survival of less than 10% (Blood 2003;102:43–52).

Disclosures: Dr. Baer reported no relevant financial relationships.

Source Elsevier Global Medical News

SNOWMASS, COLO. — A wide range of rheumatic diseases is associated with increased risk for myeloid malignancies, according to an analysis of the National Cancer Institute's Surveillance, Epidemiology and End Results database.

Epidemiologic studies such as this SEER analysis can't address causation. But it's clear that much of the increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and other rheumatic diseases is a consequence of the medications used in treating the autoimmune disease, Dr. Maria R. Baer said at a symposium sponsored by the American College of Rheumatology.

Shared genetic predisposition and extension of the rheumatic disease into the bone marrow are other possible explanations.

There is a well-established association between rheumatic conditions and an increased risk of lymphoma. The risk of myeloid malignancies in rheumatology patients has, until recently, undergone far less scrutiny, noted Dr. Baer, a hematologist and oncologist at the cancer center of the University of Maryland in Baltimore.

The retrospective, case-control SEER study, conducted by investigators at Queen's University of Belfast (Northern Ireland), incorporated 13,486 U.S. patients with myeloid malignancies and 160,086 controls.

Multiple logistic regression analyses, adjusted for potential confounders, showed that rheumatic diseases were associated with an overall 1.29-fold increased risk of AML. The AML risk varied by the specific rheumatologic disease. It was greatest in systemic vasculitis patients, who were at 6.23-fold greater risk than were controls who were free of rheumatic diseases.

On the other hand, systemic vasculitis was the only rheumatic disease included in the study that was not associated with an elevated risk of MDS. (See box.)

The autoimmune diseases weren't associated with overall increased risks of chronic myeloid leukemia or chronic myeloproliferative disorders (Br. J. Cancer 2009;100:822–8).

Another informative, large, retrospective cohort study was conducted by investigators at the California Cancer Registry. They found that in 30,478 patients with SLE who were followed for nearly 158,000 person-years, the risk of myeloid leukemia was increased 2.96-fold. The SLE patients also had a 2.7-fold increased risk of liver cancer, a 3.27-fold increased of vaginal/vulvar cancer, and elevated risks of lung, thyroid, and renal cancers (Cancer Causes Control 2008;19:887–94).

The same team of investigators subsequently studied 84,475 rheumatoid arthritis patients over an observation period stretching in excess of 405,000 person-years. The patients proved to have significantly increased risks of hematopoietic, lung, liver, and esophageal cancers. They also had lower-than-average rates of several screenable cancers, as did the SLE patients in the earlier study (Cancer Causes Control 2009;20:1001–10).

Cytotoxic therapy–related MDS and AML (abbreviated by hematologists as t-MDS and t-AML) have a readily identifiable pathological pattern. It is characterized by morphological dysplasia of the bone marrow and clonal cytogenetic abnormalities, most often loss of part or all of chromosome 5 or 7 or both. Although t-MDS often evolves into t-AML, t-AML isn't always preceded by t-MDS. The distinction between the two, as arbitrarily defined by the World Health Organization, is that t-AML features at least 20% myeloblasts, Dr. Baer continued.

Methotrexate use doesn't appear to be linked to the increased risk of t-MDS or t-AML, although it is associated with an increased risk of lymphoma.

In contrast, cyclophosphamide is a major culprit in the t-MDS and t-AML that are encountered in rheumatology patients. In what Dr. Baer termed “a classic” study, Danish investigators showed that in a cohort of 293 patients with Wegener's granulomatosis who were followed for 2,121 person-years, the risk of AML was increased 19.6-fold overall, compared with that of the general population. The risk was not elevated above that in controls for Wegener's patients who had received a cumulative 36 g or less of cyclophosphamide. However, patients who had received more than 36 g (equivalent to 100 mg/day for more than a year) had a 59-fold increased risk of AML (J. Rheumatol. 2008;35:100–5).

Both t-MDS and t-AML are “bad entities,” she emphasized. The first question to ask is whether an affected patient is a candidate for aggressive therapy with allogeneic hematopoietic stem cell transplantation—the clear treatment of choice—and if so, whether a donor is available.

“The outcome is really dismal, transplant or no transplant. You want to modulate your rheumatologic therapy to avoid this complication because it's quite devastating when it does occur,” Dr. Baer said.

She offered as one representative series a 306-patient University of Chicago cohort. Their median survival after diagnosis of t-MDS or t-AML was 8 months, with a 5-year survival of less than 10% (Blood 2003;102:43–52).

Disclosures: Dr. Baer reported no relevant financial relationships.

Source Elsevier Global Medical News

SNOWMASS, COLO. — Screening for both hepatitis C and B is a reasonable strategy in all patients who are under consideration for any disease-modifying antirheumatic drug. “If they turn out to be infected, you've done them a huge favor. Send them to a hepatologist for treatment,” advised Dr. Leonard H. Calabrese.

And just because they have chronic viral hepatitis doesn't mean that their comorbid rheumatic disease can't be aggressively treated, provided they don't have decompensated liver disease and are Child-Pugh class A, he stressed at a symposium sponsored by the American College of Rheumatology.

Evidence suggests that in chronic HCV, anti–tumor necrosis factor (anti-TNF) therapy not only is safe, it actually may also substantially improve the tolerability of antiviral therapy with interferon and ribavirin, thereby boosting the hepatitis cure rate, said Dr. Calabrese.

This possibility was first broached a half-decade ago in a positive double-blind, placebo-controlled, phase II study of etanercept (Enbrel) (J. Hepatol. 2005;42:315–22). The manufacturer resisted hepatologists' subsequent pleas to mount a definitive clinical trial. However, such a study is now underway using another anti-TNF drug, infliximab (Remicade).

The 52-week, multicenter, blinded, randomized PARTNER (Pegylated Interferon Ribavirin and Anti-TNF Enhanced Response) trial, sponsored by the Cleveland Clinic, has completed just over half of its enrollment. Eligibility is restricted to patients with chronic HCV with genotype 1, the most treatment-resistant form of the disease. These patients don't have concomitant rheumatic disease; they are being randomized to anti-TNF therapy solely in an effort to improve the results of their antiviral regimen.

However, several reports published in the literature point to the safety of anti-TNF therapy in patients with chronic HCV and comorbid rheumatic diseases. Dr. Calabrese highlighted what he termed a “thoughtful and reassuring” seven-center prospective Italian series involving 31 chronic HCV-infected patients with rheumatoid arthritis (RA) refractory to nonbiologic disease-modifying antirheumatic drugs (DMARDs). After a mean 22 months of treatment with infliximab, etanercept, or adalimumab, the patients showed marked lessening of their rheumatic disease with no adverse effects on liver enzymes or HCV viral load (J. Rheumatol. 2008;35:1944–9).

Based upon such favorable reports as well as the results of the earlier etanercept study, Dr. Calabrese reported that he turns to anti-TNF biologic agents as first-line therapy in HCV-infected patients who require remittive therapy for a rheumatic disease. He makes sure they have a baseline liver biopsy, carefully monitors their liver enzymes, and considers rebiopsy at 3-5 years.

“At this point in time, there are more data on the safety of biologics than nonbiologic DMARDs in the setting of HCV,” according to Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

The use of DMARDs in patients with chronic HBV is a considerably more complex issue. That's because there is evidence that any form of immunosuppressive therapy—biologics, older DMARDs, or moderate- or high-dose systemic corticosteroids—can trigger a severe or even fatal flare of hepatitis B if the therapy is interrupted or discontinued.

Nonetheless, there are multiple reports of HBV-infected patients who are being successfully treated for rheumatoid arthritis and other rheumatic diseases with biologic agents or conventional DMARDs, provided they are started on prophylactic antiviral therapy beforehand. For example, Italian investigators reported no cases of HBV reactivation in 20 patients with rheumatic diseases who were treated with biologic DMARDs during a median 19 months of prophylactic antiviral therapy with lamivudine at 100 mg/day (Reumatismo 2008;60:22–7).

Today, there are much better antivirals than lamivudine for this purpose, Dr. Calabrese pointed out. Nucleotide analog reverse transcriptase inhibitors such as adefovir (Preveon) and tenofovir (Viread) are very easy to use and have far fewer resistance issues. The experience to date strongly suggests that the newer agents can be given for the patient's full remaining life span.

There are at present no consensus guidelines in rheumatology that address screening for HCV and HBV. Dr. Calabrese advocated screening liberally; these are two of the biggest public health problems of the era, and treatment has progressed rapidly. He believes that all candidates for DMARD therapy ought to be screened, as well as any rheumatology patient who is at high risk for HCV or HBV. “HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected,” he said.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech Inc., Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

'HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected.'

Source DR. CALABRESE

SNOWMASS, COLO. — Screening for both hepatitis C and B is a reasonable strategy in all patients who are under consideration for any disease-modifying antirheumatic drug. “If they turn out to be infected, you've done them a huge favor. Send them to a hepatologist for treatment,” advised Dr. Leonard H. Calabrese.

And just because they have chronic viral hepatitis doesn't mean that their comorbid rheumatic disease can't be aggressively treated, provided they don't have decompensated liver disease and are Child-Pugh class A, he stressed at a symposium sponsored by the American College of Rheumatology.

Evidence suggests that in chronic HCV, anti–tumor necrosis factor (anti-TNF) therapy not only is safe, it actually may also substantially improve the tolerability of antiviral therapy with interferon and ribavirin, thereby boosting the hepatitis cure rate, said Dr. Calabrese.

This possibility was first broached a half-decade ago in a positive double-blind, placebo-controlled, phase II study of etanercept (Enbrel) (J. Hepatol. 2005;42:315–22). The manufacturer resisted hepatologists' subsequent pleas to mount a definitive clinical trial. However, such a study is now underway using another anti-TNF drug, infliximab (Remicade).

The 52-week, multicenter, blinded, randomized PARTNER (Pegylated Interferon Ribavirin and Anti-TNF Enhanced Response) trial, sponsored by the Cleveland Clinic, has completed just over half of its enrollment. Eligibility is restricted to patients with chronic HCV with genotype 1, the most treatment-resistant form of the disease. These patients don't have concomitant rheumatic disease; they are being randomized to anti-TNF therapy solely in an effort to improve the results of their antiviral regimen.

However, several reports published in the literature point to the safety of anti-TNF therapy in patients with chronic HCV and comorbid rheumatic diseases. Dr. Calabrese highlighted what he termed a “thoughtful and reassuring” seven-center prospective Italian series involving 31 chronic HCV-infected patients with rheumatoid arthritis (RA) refractory to nonbiologic disease-modifying antirheumatic drugs (DMARDs). After a mean 22 months of treatment with infliximab, etanercept, or adalimumab, the patients showed marked lessening of their rheumatic disease with no adverse effects on liver enzymes or HCV viral load (J. Rheumatol. 2008;35:1944–9).

Based upon such favorable reports as well as the results of the earlier etanercept study, Dr. Calabrese reported that he turns to anti-TNF biologic agents as first-line therapy in HCV-infected patients who require remittive therapy for a rheumatic disease. He makes sure they have a baseline liver biopsy, carefully monitors their liver enzymes, and considers rebiopsy at 3-5 years.

“At this point in time, there are more data on the safety of biologics than nonbiologic DMARDs in the setting of HCV,” according to Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

The use of DMARDs in patients with chronic HBV is a considerably more complex issue. That's because there is evidence that any form of immunosuppressive therapy—biologics, older DMARDs, or moderate- or high-dose systemic corticosteroids—can trigger a severe or even fatal flare of hepatitis B if the therapy is interrupted or discontinued.

Nonetheless, there are multiple reports of HBV-infected patients who are being successfully treated for rheumatoid arthritis and other rheumatic diseases with biologic agents or conventional DMARDs, provided they are started on prophylactic antiviral therapy beforehand. For example, Italian investigators reported no cases of HBV reactivation in 20 patients with rheumatic diseases who were treated with biologic DMARDs during a median 19 months of prophylactic antiviral therapy with lamivudine at 100 mg/day (Reumatismo 2008;60:22–7).

Today, there are much better antivirals than lamivudine for this purpose, Dr. Calabrese pointed out. Nucleotide analog reverse transcriptase inhibitors such as adefovir (Preveon) and tenofovir (Viread) are very easy to use and have far fewer resistance issues. The experience to date strongly suggests that the newer agents can be given for the patient's full remaining life span.

There are at present no consensus guidelines in rheumatology that address screening for HCV and HBV. Dr. Calabrese advocated screening liberally; these are two of the biggest public health problems of the era, and treatment has progressed rapidly. He believes that all candidates for DMARD therapy ought to be screened, as well as any rheumatology patient who is at high risk for HCV or HBV. “HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected,” he said.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech Inc., Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

'HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected.'

Source DR. CALABRESE

SNOWMASS, COLO. — Screening for both hepatitis C and B is a reasonable strategy in all patients who are under consideration for any disease-modifying antirheumatic drug. “If they turn out to be infected, you've done them a huge favor. Send them to a hepatologist for treatment,” advised Dr. Leonard H. Calabrese.

And just because they have chronic viral hepatitis doesn't mean that their comorbid rheumatic disease can't be aggressively treated, provided they don't have decompensated liver disease and are Child-Pugh class A, he stressed at a symposium sponsored by the American College of Rheumatology.

Evidence suggests that in chronic HCV, anti–tumor necrosis factor (anti-TNF) therapy not only is safe, it actually may also substantially improve the tolerability of antiviral therapy with interferon and ribavirin, thereby boosting the hepatitis cure rate, said Dr. Calabrese.

This possibility was first broached a half-decade ago in a positive double-blind, placebo-controlled, phase II study of etanercept (Enbrel) (J. Hepatol. 2005;42:315–22). The manufacturer resisted hepatologists' subsequent pleas to mount a definitive clinical trial. However, such a study is now underway using another anti-TNF drug, infliximab (Remicade).

The 52-week, multicenter, blinded, randomized PARTNER (Pegylated Interferon Ribavirin and Anti-TNF Enhanced Response) trial, sponsored by the Cleveland Clinic, has completed just over half of its enrollment. Eligibility is restricted to patients with chronic HCV with genotype 1, the most treatment-resistant form of the disease. These patients don't have concomitant rheumatic disease; they are being randomized to anti-TNF therapy solely in an effort to improve the results of their antiviral regimen.

However, several reports published in the literature point to the safety of anti-TNF therapy in patients with chronic HCV and comorbid rheumatic diseases. Dr. Calabrese highlighted what he termed a “thoughtful and reassuring” seven-center prospective Italian series involving 31 chronic HCV-infected patients with rheumatoid arthritis (RA) refractory to nonbiologic disease-modifying antirheumatic drugs (DMARDs). After a mean 22 months of treatment with infliximab, etanercept, or adalimumab, the patients showed marked lessening of their rheumatic disease with no adverse effects on liver enzymes or HCV viral load (J. Rheumatol. 2008;35:1944–9).

Based upon such favorable reports as well as the results of the earlier etanercept study, Dr. Calabrese reported that he turns to anti-TNF biologic agents as first-line therapy in HCV-infected patients who require remittive therapy for a rheumatic disease. He makes sure they have a baseline liver biopsy, carefully monitors their liver enzymes, and considers rebiopsy at 3-5 years.

“At this point in time, there are more data on the safety of biologics than nonbiologic DMARDs in the setting of HCV,” according to Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

The use of DMARDs in patients with chronic HBV is a considerably more complex issue. That's because there is evidence that any form of immunosuppressive therapy—biologics, older DMARDs, or moderate- or high-dose systemic corticosteroids—can trigger a severe or even fatal flare of hepatitis B if the therapy is interrupted or discontinued.

Nonetheless, there are multiple reports of HBV-infected patients who are being successfully treated for rheumatoid arthritis and other rheumatic diseases with biologic agents or conventional DMARDs, provided they are started on prophylactic antiviral therapy beforehand. For example, Italian investigators reported no cases of HBV reactivation in 20 patients with rheumatic diseases who were treated with biologic DMARDs during a median 19 months of prophylactic antiviral therapy with lamivudine at 100 mg/day (Reumatismo 2008;60:22–7).

Today, there are much better antivirals than lamivudine for this purpose, Dr. Calabrese pointed out. Nucleotide analog reverse transcriptase inhibitors such as adefovir (Preveon) and tenofovir (Viread) are very easy to use and have far fewer resistance issues. The experience to date strongly suggests that the newer agents can be given for the patient's full remaining life span.

There are at present no consensus guidelines in rheumatology that address screening for HCV and HBV. Dr. Calabrese advocated screening liberally; these are two of the biggest public health problems of the era, and treatment has progressed rapidly. He believes that all candidates for DMARD therapy ought to be screened, as well as any rheumatology patient who is at high risk for HCV or HBV. “HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected,” he said.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech Inc., Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

'HBsAg is what you're really looking for. If you're positive, you're a carrier, and you're infected.'

Source DR. CALABRESE

SNOWMASS, COLO. — Corticosteroids can be thought of as the “go-to” drugs for the management of rheumatologic disorders in pregnancy.

“Corticosteroids have been my ace in the hole in treating many patients during pregnancy. They're potent immunosuppressives that can get you out of a lot of trouble. And although they can have side effects, if used judiciously they are a reasonable treatment choice,” Dr. Bonnie L. Bermas stressed at a symposium sponsored by the American College of Rheumatology.

Transplant registries comprising tens of thousands of organ recipients have shown no increased rate of congenital anomalies with the use of corticosteroids in pregnancy. However, an influential University of Toronto meta-analysis concluded that “although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft” (Teratology 2000;62:385–92).

“What this translates to in your practice is, the cleft palate incidence increases from 1 in 1,000 in the general population to about 1 in 300 live births exposed to steroids in utero. That's how I counsel my patients who need to be on corticosteroids in the first trimester,” said Dr. Bermas, clinical director of the lupus center at Brigham and Women's Hospital in Boston.

After 12-14 weeks' gestation, the palate is formed; steroids are no longer associated with an increased risk for cleft palate after that point. But other risks remain, including gestational diabetes, gestational hypertension, osteoporosis in the mother, premature rupture of the membranes, and small-for-gestational-age infants. Prednisone and methylprednisolone—the steroids rheumatologists utilize most often—don't cross the placenta efficiently, and are much less likely to cause fetal adverse effects than are dexamethasone or betamethasone.

Steroids that are administered to the mother make their way into breast milk only in low concentrations. If she's on less than 20 mg/day of prednisone, she can breastfeed normally. For women on higher doses, Dr. Bermas advises pumping and discarding the breast milk for the first 4 hours after a dose is taken.

The key to successful treatment of rheumatologic disorders during pregnancy is a clear assessment of the patient's tolerance for risk—and the physician's, as well, Dr. Bermas said. “There are some women who do not drink caffeinated beverages or take any medications, not even a Tylenol, and who will eat only organic foods while pregnant.…And as clinicians, we have our own risk tolerances, too. For example, azathioprine is a medication that I feel comfortable using during pregnancy, but I have colleagues who won't because they wouldn't be able to sleep at night,” she said.

The reason she prescribes azathioprine during pregnancy—despite its category D rating from the Food and Drug Administration, indicating “positive evidence of risk”—is that there's an enormous transplant literature showing no increase in congenital anomalies with in utero exposure to this drug. Mycophenolate mofetil (CellCept) also has a category D rating. But unlike azathioprine, it has no extensive and reassuring transplant literature, so Dr. Bermas said she avoids it in pregnant and nursing patients.

Other rheumatologic medications to avoid in pregnancy are methotrexate, penicillamine, 6-mercaptopurine, and chlorambucil, she continued.

The use of tumor necrosis factor inhibitors during pregnancy is an extremely challenging question. Although at present the FDA rates them as category B (“no evidence of risk in humans”), that could very well change as a result of a reported association (J. Rheumatol. 2009;36:635–41) with VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) anomalies.

When lupus patients on antimalarials become pregnant, Dr. Bermas said she generally keeps them on the medication. She also allows patients to remain on antimalarials while nursing, which is consistent with the position of the American Academy of Pediatrics.

For mild cases of rheumatologic disease in pregnancy, Dr. Bermas said that she relies on NSAIDs and/or prednisone at 5-10 mg/day. She halts the NSAID after the second trimester in order to avoid premature closure of a patent ductus arteriosus. For an inflammatory mild arthritis, she considers adding sulfasalazine.

She manages moderate disease with higher-dose steroids, azathioprine, or cyclosporine. For severe disease, Dr. Bermas reported that she turns to pulse steroids, azathioprine, cyclosporine, or intravenous immunoglobulin. In life-or-death situations, there are many case reports of cyclophosphamide being used successfully in the third trimester, a time by which most organogenesis is completed.

Disclosures: Dr. Bermas reported having no financial conflicts of interest.

Corticosteroids are potent and 'can get you out of a lot of trouble,' even with their side effects.

Source DR. BERMAS

SNOWMASS, COLO. — Corticosteroids can be thought of as the “go-to” drugs for the management of rheumatologic disorders in pregnancy.

“Corticosteroids have been my ace in the hole in treating many patients during pregnancy. They're potent immunosuppressives that can get you out of a lot of trouble. And although they can have side effects, if used judiciously they are a reasonable treatment choice,” Dr. Bonnie L. Bermas stressed at a symposium sponsored by the American College of Rheumatology.

Transplant registries comprising tens of thousands of organ recipients have shown no increased rate of congenital anomalies with the use of corticosteroids in pregnancy. However, an influential University of Toronto meta-analysis concluded that “although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft” (Teratology 2000;62:385–92).

“What this translates to in your practice is, the cleft palate incidence increases from 1 in 1,000 in the general population to about 1 in 300 live births exposed to steroids in utero. That's how I counsel my patients who need to be on corticosteroids in the first trimester,” said Dr. Bermas, clinical director of the lupus center at Brigham and Women's Hospital in Boston.

After 12-14 weeks' gestation, the palate is formed; steroids are no longer associated with an increased risk for cleft palate after that point. But other risks remain, including gestational diabetes, gestational hypertension, osteoporosis in the mother, premature rupture of the membranes, and small-for-gestational-age infants. Prednisone and methylprednisolone—the steroids rheumatologists utilize most often—don't cross the placenta efficiently, and are much less likely to cause fetal adverse effects than are dexamethasone or betamethasone.

Steroids that are administered to the mother make their way into breast milk only in low concentrations. If she's on less than 20 mg/day of prednisone, she can breastfeed normally. For women on higher doses, Dr. Bermas advises pumping and discarding the breast milk for the first 4 hours after a dose is taken.

The key to successful treatment of rheumatologic disorders during pregnancy is a clear assessment of the patient's tolerance for risk—and the physician's, as well, Dr. Bermas said. “There are some women who do not drink caffeinated beverages or take any medications, not even a Tylenol, and who will eat only organic foods while pregnant.…And as clinicians, we have our own risk tolerances, too. For example, azathioprine is a medication that I feel comfortable using during pregnancy, but I have colleagues who won't because they wouldn't be able to sleep at night,” she said.

The reason she prescribes azathioprine during pregnancy—despite its category D rating from the Food and Drug Administration, indicating “positive evidence of risk”—is that there's an enormous transplant literature showing no increase in congenital anomalies with in utero exposure to this drug. Mycophenolate mofetil (CellCept) also has a category D rating. But unlike azathioprine, it has no extensive and reassuring transplant literature, so Dr. Bermas said she avoids it in pregnant and nursing patients.

Other rheumatologic medications to avoid in pregnancy are methotrexate, penicillamine, 6-mercaptopurine, and chlorambucil, she continued.

The use of tumor necrosis factor inhibitors during pregnancy is an extremely challenging question. Although at present the FDA rates them as category B (“no evidence of risk in humans”), that could very well change as a result of a reported association (J. Rheumatol. 2009;36:635–41) with VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) anomalies.

When lupus patients on antimalarials become pregnant, Dr. Bermas said she generally keeps them on the medication. She also allows patients to remain on antimalarials while nursing, which is consistent with the position of the American Academy of Pediatrics.

For mild cases of rheumatologic disease in pregnancy, Dr. Bermas said that she relies on NSAIDs and/or prednisone at 5-10 mg/day. She halts the NSAID after the second trimester in order to avoid premature closure of a patent ductus arteriosus. For an inflammatory mild arthritis, she considers adding sulfasalazine.

She manages moderate disease with higher-dose steroids, azathioprine, or cyclosporine. For severe disease, Dr. Bermas reported that she turns to pulse steroids, azathioprine, cyclosporine, or intravenous immunoglobulin. In life-or-death situations, there are many case reports of cyclophosphamide being used successfully in the third trimester, a time by which most organogenesis is completed.

Disclosures: Dr. Bermas reported having no financial conflicts of interest.

Corticosteroids are potent and 'can get you out of a lot of trouble,' even with their side effects.

Source DR. BERMAS

SNOWMASS, COLO. — Corticosteroids can be thought of as the “go-to” drugs for the management of rheumatologic disorders in pregnancy.

“Corticosteroids have been my ace in the hole in treating many patients during pregnancy. They're potent immunosuppressives that can get you out of a lot of trouble. And although they can have side effects, if used judiciously they are a reasonable treatment choice,” Dr. Bonnie L. Bermas stressed at a symposium sponsored by the American College of Rheumatology.

Transplant registries comprising tens of thousands of organ recipients have shown no increased rate of congenital anomalies with the use of corticosteroids in pregnancy. However, an influential University of Toronto meta-analysis concluded that “although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft” (Teratology 2000;62:385–92).

“What this translates to in your practice is, the cleft palate incidence increases from 1 in 1,000 in the general population to about 1 in 300 live births exposed to steroids in utero. That's how I counsel my patients who need to be on corticosteroids in the first trimester,” said Dr. Bermas, clinical director of the lupus center at Brigham and Women's Hospital in Boston.

After 12-14 weeks' gestation, the palate is formed; steroids are no longer associated with an increased risk for cleft palate after that point. But other risks remain, including gestational diabetes, gestational hypertension, osteoporosis in the mother, premature rupture of the membranes, and small-for-gestational-age infants. Prednisone and methylprednisolone—the steroids rheumatologists utilize most often—don't cross the placenta efficiently, and are much less likely to cause fetal adverse effects than are dexamethasone or betamethasone.

Steroids that are administered to the mother make their way into breast milk only in low concentrations. If she's on less than 20 mg/day of prednisone, she can breastfeed normally. For women on higher doses, Dr. Bermas advises pumping and discarding the breast milk for the first 4 hours after a dose is taken.

The key to successful treatment of rheumatologic disorders during pregnancy is a clear assessment of the patient's tolerance for risk—and the physician's, as well, Dr. Bermas said. “There are some women who do not drink caffeinated beverages or take any medications, not even a Tylenol, and who will eat only organic foods while pregnant.…And as clinicians, we have our own risk tolerances, too. For example, azathioprine is a medication that I feel comfortable using during pregnancy, but I have colleagues who won't because they wouldn't be able to sleep at night,” she said.

The reason she prescribes azathioprine during pregnancy—despite its category D rating from the Food and Drug Administration, indicating “positive evidence of risk”—is that there's an enormous transplant literature showing no increase in congenital anomalies with in utero exposure to this drug. Mycophenolate mofetil (CellCept) also has a category D rating. But unlike azathioprine, it has no extensive and reassuring transplant literature, so Dr. Bermas said she avoids it in pregnant and nursing patients.

Other rheumatologic medications to avoid in pregnancy are methotrexate, penicillamine, 6-mercaptopurine, and chlorambucil, she continued.

The use of tumor necrosis factor inhibitors during pregnancy is an extremely challenging question. Although at present the FDA rates them as category B (“no evidence of risk in humans”), that could very well change as a result of a reported association (J. Rheumatol. 2009;36:635–41) with VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, and limb) anomalies.

When lupus patients on antimalarials become pregnant, Dr. Bermas said she generally keeps them on the medication. She also allows patients to remain on antimalarials while nursing, which is consistent with the position of the American Academy of Pediatrics.

For mild cases of rheumatologic disease in pregnancy, Dr. Bermas said that she relies on NSAIDs and/or prednisone at 5-10 mg/day. She halts the NSAID after the second trimester in order to avoid premature closure of a patent ductus arteriosus. For an inflammatory mild arthritis, she considers adding sulfasalazine.

She manages moderate disease with higher-dose steroids, azathioprine, or cyclosporine. For severe disease, Dr. Bermas reported that she turns to pulse steroids, azathioprine, cyclosporine, or intravenous immunoglobulin. In life-or-death situations, there are many case reports of cyclophosphamide being used successfully in the third trimester, a time by which most organogenesis is completed.

Disclosures: Dr. Bermas reported having no financial conflicts of interest.

Corticosteroids are potent and 'can get you out of a lot of trouble,' even with their side effects.

Source DR. BERMAS

SNOWMASS, COLO. — Tocilizumab has a “liver signal” that's likely to cause headaches for rheumatologists.

The problem arises from the associated high frequency of elevated liver function tests when tocilizumab (Actemra) is prescribed with methotrexate, a combination that was specifically okayed under both Food and Drug Administration and European Medicines Agency indications, Dr. Leonard H. Calabrese said at a symposium sponsored by the American College of Rheumatology.

The existing guidelines for methotrexate are not going to work as well when the drug is used in combination with tocilizumab. Because of the high rate of elevated liver enzymes, the guidelines are going to need to be reworked, predicted Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

Dr. Calabrese stressed that to date, the liver toxicity data for tocilizumab are “reasonably reassuring”: The vast majority of cases of increased liver enzyme levels are mild, with elevations no more than three times the upper limit of normal. The elevations are transient, and levels return to normal without treatment discontinuation or even dose adjustment. No serious drug-induced hepatotoxicity has been observed in more than 4,100 patient-years of exposure, nor has direct hyperbilirubinemia been seen.

That said, it's important to recognize that drug-induced serious hepatotoxicity is a rare event that often goes unrecognized until after a drug reaches the broader market. In fact, despite its rarity, hepatotoxicity is the No. 1 cause for withdrawal of drugs from the marketplace, Dr. Calabrese continued.

The approved indication for tocilizumab is treatment of moderate to severe rheumatoid arthritis in patients with an inadequate response to one or more tumor necrosis factor blockers. Tocilizumab, a once-monthly intravenous agent, may be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. The FDA has required Genentech Inc. to implement a REMS (Risk Evaluation and Mitigation Strategy) that includes a plan to inform physicians how to monitor for liver and other GI side effects.

The tocilizumab label advises patients to tell their physicians of any preexisting liver problems, and alerts them to the need for liver function tests before and during therapy. Information included on the label in January 2010 warns of the possibility of elevated ALT in patients on the drug.

Clinical trials demonstrate that tocilizumab as monotherapy has a rate of elevated liver function tests similar to that of methotrexate monotherapy. When the drugs are used in combination, however, mildly elevated liver enzymes have occurred in one-third to nearly one-half of patients in the various studies.

It's not surprising that tocilizumab—a humanized monoclonal antibody directed against the interleukin-6 receptor—has displayed an early liver signal, in Dr. Calabrese's view. Hepatocytes express IL-6, a pleiotropic cytokine with numerous effects that are important to homeostatic regulation of the liver. Tocilizumab inhibits the STAT3 (signal transducer and activator of transcription 3) pathway, which plays a key role in blocking apoptotic injury to the liver. In animal studies, impedance of the STAT3 pathway greatly reduced the liver's ability to buffer injury resulting from alcohol and various other stressors.

As for the hepatic side effects of the other biologic agents used in rheumatology, infliximab (Remicade) carries the strongest warning language from the FDA. “Infliximab is an exception to the anti-TNF class. It's the only one that has a small liver signal even within the confines of clinical trials,” Dr. Calabrese said.

All of the TNF blockers have been linked to rare postmarketing reports of autoimmune hepatitis or other forms of severe hepatotoxicity, but infliximab is the one that has come up most frequently.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech, Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

SNOWMASS, COLO. — Tocilizumab has a “liver signal” that's likely to cause headaches for rheumatologists.

The problem arises from the associated high frequency of elevated liver function tests when tocilizumab (Actemra) is prescribed with methotrexate, a combination that was specifically okayed under both Food and Drug Administration and European Medicines Agency indications, Dr. Leonard H. Calabrese said at a symposium sponsored by the American College of Rheumatology.

The existing guidelines for methotrexate are not going to work as well when the drug is used in combination with tocilizumab. Because of the high rate of elevated liver enzymes, the guidelines are going to need to be reworked, predicted Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

Dr. Calabrese stressed that to date, the liver toxicity data for tocilizumab are “reasonably reassuring”: The vast majority of cases of increased liver enzyme levels are mild, with elevations no more than three times the upper limit of normal. The elevations are transient, and levels return to normal without treatment discontinuation or even dose adjustment. No serious drug-induced hepatotoxicity has been observed in more than 4,100 patient-years of exposure, nor has direct hyperbilirubinemia been seen.

That said, it's important to recognize that drug-induced serious hepatotoxicity is a rare event that often goes unrecognized until after a drug reaches the broader market. In fact, despite its rarity, hepatotoxicity is the No. 1 cause for withdrawal of drugs from the marketplace, Dr. Calabrese continued.

The approved indication for tocilizumab is treatment of moderate to severe rheumatoid arthritis in patients with an inadequate response to one or more tumor necrosis factor blockers. Tocilizumab, a once-monthly intravenous agent, may be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. The FDA has required Genentech Inc. to implement a REMS (Risk Evaluation and Mitigation Strategy) that includes a plan to inform physicians how to monitor for liver and other GI side effects.

The tocilizumab label advises patients to tell their physicians of any preexisting liver problems, and alerts them to the need for liver function tests before and during therapy. Information included on the label in January 2010 warns of the possibility of elevated ALT in patients on the drug.

Clinical trials demonstrate that tocilizumab as monotherapy has a rate of elevated liver function tests similar to that of methotrexate monotherapy. When the drugs are used in combination, however, mildly elevated liver enzymes have occurred in one-third to nearly one-half of patients in the various studies.

It's not surprising that tocilizumab—a humanized monoclonal antibody directed against the interleukin-6 receptor—has displayed an early liver signal, in Dr. Calabrese's view. Hepatocytes express IL-6, a pleiotropic cytokine with numerous effects that are important to homeostatic regulation of the liver. Tocilizumab inhibits the STAT3 (signal transducer and activator of transcription 3) pathway, which plays a key role in blocking apoptotic injury to the liver. In animal studies, impedance of the STAT3 pathway greatly reduced the liver's ability to buffer injury resulting from alcohol and various other stressors.

As for the hepatic side effects of the other biologic agents used in rheumatology, infliximab (Remicade) carries the strongest warning language from the FDA. “Infliximab is an exception to the anti-TNF class. It's the only one that has a small liver signal even within the confines of clinical trials,” Dr. Calabrese said.

All of the TNF blockers have been linked to rare postmarketing reports of autoimmune hepatitis or other forms of severe hepatotoxicity, but infliximab is the one that has come up most frequently.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech, Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

SNOWMASS, COLO. — Tocilizumab has a “liver signal” that's likely to cause headaches for rheumatologists.

The problem arises from the associated high frequency of elevated liver function tests when tocilizumab (Actemra) is prescribed with methotrexate, a combination that was specifically okayed under both Food and Drug Administration and European Medicines Agency indications, Dr. Leonard H. Calabrese said at a symposium sponsored by the American College of Rheumatology.

The existing guidelines for methotrexate are not going to work as well when the drug is used in combination with tocilizumab. Because of the high rate of elevated liver enzymes, the guidelines are going to need to be reworked, predicted Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.

Dr. Calabrese stressed that to date, the liver toxicity data for tocilizumab are “reasonably reassuring”: The vast majority of cases of increased liver enzyme levels are mild, with elevations no more than three times the upper limit of normal. The elevations are transient, and levels return to normal without treatment discontinuation or even dose adjustment. No serious drug-induced hepatotoxicity has been observed in more than 4,100 patient-years of exposure, nor has direct hyperbilirubinemia been seen.

That said, it's important to recognize that drug-induced serious hepatotoxicity is a rare event that often goes unrecognized until after a drug reaches the broader market. In fact, despite its rarity, hepatotoxicity is the No. 1 cause for withdrawal of drugs from the marketplace, Dr. Calabrese continued.

The approved indication for tocilizumab is treatment of moderate to severe rheumatoid arthritis in patients with an inadequate response to one or more tumor necrosis factor blockers. Tocilizumab, a once-monthly intravenous agent, may be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. The FDA has required Genentech Inc. to implement a REMS (Risk Evaluation and Mitigation Strategy) that includes a plan to inform physicians how to monitor for liver and other GI side effects.

The tocilizumab label advises patients to tell their physicians of any preexisting liver problems, and alerts them to the need for liver function tests before and during therapy. Information included on the label in January 2010 warns of the possibility of elevated ALT in patients on the drug.

Clinical trials demonstrate that tocilizumab as monotherapy has a rate of elevated liver function tests similar to that of methotrexate monotherapy. When the drugs are used in combination, however, mildly elevated liver enzymes have occurred in one-third to nearly one-half of patients in the various studies.

It's not surprising that tocilizumab—a humanized monoclonal antibody directed against the interleukin-6 receptor—has displayed an early liver signal, in Dr. Calabrese's view. Hepatocytes express IL-6, a pleiotropic cytokine with numerous effects that are important to homeostatic regulation of the liver. Tocilizumab inhibits the STAT3 (signal transducer and activator of transcription 3) pathway, which plays a key role in blocking apoptotic injury to the liver. In animal studies, impedance of the STAT3 pathway greatly reduced the liver's ability to buffer injury resulting from alcohol and various other stressors.

As for the hepatic side effects of the other biologic agents used in rheumatology, infliximab (Remicade) carries the strongest warning language from the FDA. “Infliximab is an exception to the anti-TNF class. It's the only one that has a small liver signal even within the confines of clinical trials,” Dr. Calabrese said.

All of the TNF blockers have been linked to rare postmarketing reports of autoimmune hepatitis or other forms of severe hepatotoxicity, but infliximab is the one that has come up most frequently.

Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech, Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.

A new “inside-out” hypothesis on the pathogenesis of rheumatoid arthritis suggests that joint damage may arise from within adjacent bone marrow, rather than—or in addition to—arising from outside via the synovial membrane, according to Dr. Georg Schett and Dr. Gary S. Firestein and published online in the journal Annals of the Rheumatic Diseases.

The conventional “outside-in” hypothesis holds that the primary pathogenic event in RA is the alteration of a synovial membrane. The altered membrane recruits immune cells, resulting in an onslaught of inflammation, cell accumulation from unbalanced proliferation and cell death, and perhaps a synovial immune response.

Either of two scenarios could lead to alterations in the synovial membrane. In one scenario, there's a confluence of environmental and genetic factors and the breakdown of tolerance. Alternatively, the synovial membrane could be changed by systemic processes.

The inside-out hypothesis holds that lesions within the bone marrow could begin to destroy the inner cortical bone surface, eventually opening pathways to the synovium. Mesenchymal elements could migrate through these cortical pores, stimulating joint inflammation, wrote Dr. Schett, professor of internal medicine, rheumatology, immunology, and oncology at the University of Erlangen-Nuremberg (Germany), and Dr. Firestein, professor of medicine of the University of California, San Diego.

Lesions within the bone marrow have been observed with MRI in the earliest stages of the disease. Microscopically, these lesions are sites where bone marrow fat has been replaced by inflammatory tissue dominated by lymphocytes. Other studies have demonstrated that these lesions are associated with structural damage in joints. “Different forms of arthritis may preferentially use either the outside-in or inside-out mechanism.…Preference for one of these two mechanisms may better explain some of the clinical differences of the various forms of arthritis.” (Arch. Rheum. Dis. 2010 March 18 [doi:10.1136/ard.2009.121657

Disclosures: The investigators stated that they had no conflicts of interest.

A new “inside-out” hypothesis on the pathogenesis of rheumatoid arthritis suggests that joint damage may arise from within adjacent bone marrow, rather than—or in addition to—arising from outside via the synovial membrane, according to Dr. Georg Schett and Dr. Gary S. Firestein and published online in the journal Annals of the Rheumatic Diseases.

The conventional “outside-in” hypothesis holds that the primary pathogenic event in RA is the alteration of a synovial membrane. The altered membrane recruits immune cells, resulting in an onslaught of inflammation, cell accumulation from unbalanced proliferation and cell death, and perhaps a synovial immune response.

Either of two scenarios could lead to alterations in the synovial membrane. In one scenario, there's a confluence of environmental and genetic factors and the breakdown of tolerance. Alternatively, the synovial membrane could be changed by systemic processes.

The inside-out hypothesis holds that lesions within the bone marrow could begin to destroy the inner cortical bone surface, eventually opening pathways to the synovium. Mesenchymal elements could migrate through these cortical pores, stimulating joint inflammation, wrote Dr. Schett, professor of internal medicine, rheumatology, immunology, and oncology at the University of Erlangen-Nuremberg (Germany), and Dr. Firestein, professor of medicine of the University of California, San Diego.

Lesions within the bone marrow have been observed with MRI in the earliest stages of the disease. Microscopically, these lesions are sites where bone marrow fat has been replaced by inflammatory tissue dominated by lymphocytes. Other studies have demonstrated that these lesions are associated with structural damage in joints. “Different forms of arthritis may preferentially use either the outside-in or inside-out mechanism.…Preference for one of these two mechanisms may better explain some of the clinical differences of the various forms of arthritis.” (Arch. Rheum. Dis. 2010 March 18 [doi:10.1136/ard.2009.121657

Disclosures: The investigators stated that they had no conflicts of interest.

A new “inside-out” hypothesis on the pathogenesis of rheumatoid arthritis suggests that joint damage may arise from within adjacent bone marrow, rather than—or in addition to—arising from outside via the synovial membrane, according to Dr. Georg Schett and Dr. Gary S. Firestein and published online in the journal Annals of the Rheumatic Diseases.

The conventional “outside-in” hypothesis holds that the primary pathogenic event in RA is the alteration of a synovial membrane. The altered membrane recruits immune cells, resulting in an onslaught of inflammation, cell accumulation from unbalanced proliferation and cell death, and perhaps a synovial immune response.

Either of two scenarios could lead to alterations in the synovial membrane. In one scenario, there's a confluence of environmental and genetic factors and the breakdown of tolerance. Alternatively, the synovial membrane could be changed by systemic processes.

The inside-out hypothesis holds that lesions within the bone marrow could begin to destroy the inner cortical bone surface, eventually opening pathways to the synovium. Mesenchymal elements could migrate through these cortical pores, stimulating joint inflammation, wrote Dr. Schett, professor of internal medicine, rheumatology, immunology, and oncology at the University of Erlangen-Nuremberg (Germany), and Dr. Firestein, professor of medicine of the University of California, San Diego.

Lesions within the bone marrow have been observed with MRI in the earliest stages of the disease. Microscopically, these lesions are sites where bone marrow fat has been replaced by inflammatory tissue dominated by lymphocytes. Other studies have demonstrated that these lesions are associated with structural damage in joints. “Different forms of arthritis may preferentially use either the outside-in or inside-out mechanism.…Preference for one of these two mechanisms may better explain some of the clinical differences of the various forms of arthritis.” (Arch. Rheum. Dis. 2010 March 18 [doi:10.1136/ard.2009.121657

Disclosures: The investigators stated that they had no conflicts of interest.

MONTREAL — Occurance of injury, heavy lifting, severe infection, or other forms of trauma were associated with the progression of psoriasis to psoriatic arthritis in a study presented at the annual meeting of the Canadian Rheumatology Association.

“All we're talking about here is an association; we can't infer causation,” Dr. Dafna Gladman, the study's principal investigator, told Rheumatology News.

Previous, less rigorous studies have suggested the association between trauma and psoriatic arthritis (PsA), said Dr. Gladman, professor of medicine at the University of Toronto and deputy director of the Centre for Prognosis Studies in the Rheumatic Diseases in that city.

“This study supports that notion—that environmental factors are important—but we think genetic factors are also involved,” as well as immunologic factors, she said, explaining that at most, 30% of psoriasis patients go on to develop PsA.

Her study, which was presented as a poster at the meeting, compared 159 patients who had PsA with the same number of control patients who had psoriasis alone, in order to identify risk factors for progression to PsA. Men accounted for a similar percentage of both groups (46% in the PsA group and 44% in the controls).

The mean age of participants in each group was similar (45 years and 48 years, respectively) as was the mean duration of psoriasis (17.5 years and 18.5 years, respectively). The mean duration of PsA was 3 years.

A questionnaire was administered to all patients to assess their environmental exposure over the past 10 years, including occupational trauma, infection, immunization, smoking status and history, and psychological stress.

Univariate and multivariate logistic regression analysis was used to determine the odds ratio of each exposure prior to the diagnosis of PsA. “We actually examined all the patients with psoriasis to make sure they didn't have psoriatic arthritis,” she said.

Univariate analysis revealed that a history of infection requiring hospitalization was the strongest risk factor for the development of PsA, with an OR of 11.7. (Infective diarrhea carried an OR of 2.11.)

The second-highest risk factor was in the category of occupational exposure. A history of work involving cumulative lifting of at least 100 lb/hr carried an OR of 2.9, and pushing cumulative loads of at least 200 lb/hr carried an OR of 1.8.

And the third-highest risk factor was any injury requiring medical attention (OR, 2.43).

Multivariate analysis revealed that injuries requiring medical attention but excluding fracture and motor vehicle accident (OR, 2.3; P = .03), occupations requiring the lifting of heavy loads (OR, 2.7; P = .002), and severe infection requiring hospitalization (OR, 10.6; P = .03) were significantly associated with progression from psoriasis to PsA.

“For exposure to immunizations we found no risk, but another group [of investigators] has found that immunization was higher in those who got arthritis,” said Dr. Gladman.

“And psychological stress had no impact, although it has been reported that psoriatic patients without arthritis have a lot of stress; in fact, they may even have more because it turns out that patients with psoriasis and no arthritis actually have worse psoriasis.”

After the multifactorial analysis, smoking appeared to be associated with decreased risk, she added. Current smoking had an OR of 0.4 (P = .01), and past smoking had an OR of 0.5 (P = .04).

Dr. Gladman said that the findings are too preliminary to inform clinical recommendations at this time, but psoriasis patients should know that “if you have a job that requires a lot of lifting, you are more susceptible to getting psoriatic arthritis. Whether it's the only factor, we don't know, because there are also genetic factors involved. It's quite possible that in those people who are genetically predisposed, if they also do this work, they are more likely to get arthritis.” She said that the next step should be to look at genetic and environmental factors and see if they are independent or not.

Disclosures: Dr. Gladman declared no conflicts of interest.

Changes in the interphalangeal joints are shown in this x-ray of a patient with PsA in both hands.

Source © 2010 National Medical Slide Bank/Custom Medical Stock Photo, All Rights Reserved

My Take

Now We Need Prospective Trials

The potential impact of trauma on the development of psoriatic arthritis was first proposed over 50 years ago, when the observation of acryo-osteolysis in an injured digit was labeled “deep Koebner's effect.”

Two recent, retrospective, case-control studies analyzed the relationship between trauma and the onset of psoriatic arthritis. Corticosteroid use (in the first report) and immunization, moving house, and injury severe enough to require medical consultation (in the second report) were associated with incident PsA.

Dr. Gladman's study provides additional support for the association between trauma and incident PsA.

In this study, individuals with PsA were matched to psoriasis patients, and investigators found that injury requiring medical attention, heavy lifting, and severe infection were associated with the development of PsA.

Of course, many important questions remain to be addressed.

Could the retrospective designs of these case-control studies be strongly influenced by recall bias? This is possible but unlikely to account for these findings, given that both RA and psoriasis subjects have been used as controls.

A second question centers on the mechanisms that underlie this interesting association.

Two potential explanations have been suggested: the activation of proinflammatory molecules (such as nerve growth factor) that are produced in the psoriatic plaques, or high-level biomechanical stress to the synovial-entheseal complex, which triggers an innate immune response and subsequent inflammation.

Evidence amassed from several different sources supports the concept that trauma may be associated with the onset of PsA.

An adequately powered prospective study of psoriasis patients, with strict case definitions and appropriate control groups, will be required to adequately test the hypothesis and to understand the magnitude of a particular risk factor. Genetic risk factors could also be analyzed in such a study.

In the meantime, we await the details of Dr. Gladman's analysis, and we should make an effort to catalogue the events that are temporally related to the onset of inflammatory arthritis in our patients.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine at the University of Rochester (N.Y.). He reports having no relevant conflicts of interest.

MONTREAL — Occurance of injury, heavy lifting, severe infection, or other forms of trauma were associated with the progression of psoriasis to psoriatic arthritis in a study presented at the annual meeting of the Canadian Rheumatology Association.

“All we're talking about here is an association; we can't infer causation,” Dr. Dafna Gladman, the study's principal investigator, told Rheumatology News.

Previous, less rigorous studies have suggested the association between trauma and psoriatic arthritis (PsA), said Dr. Gladman, professor of medicine at the University of Toronto and deputy director of the Centre for Prognosis Studies in the Rheumatic Diseases in that city.

“This study supports that notion—that environmental factors are important—but we think genetic factors are also involved,” as well as immunologic factors, she said, explaining that at most, 30% of psoriasis patients go on to develop PsA.

Her study, which was presented as a poster at the meeting, compared 159 patients who had PsA with the same number of control patients who had psoriasis alone, in order to identify risk factors for progression to PsA. Men accounted for a similar percentage of both groups (46% in the PsA group and 44% in the controls).

The mean age of participants in each group was similar (45 years and 48 years, respectively) as was the mean duration of psoriasis (17.5 years and 18.5 years, respectively). The mean duration of PsA was 3 years.

A questionnaire was administered to all patients to assess their environmental exposure over the past 10 years, including occupational trauma, infection, immunization, smoking status and history, and psychological stress.

Univariate and multivariate logistic regression analysis was used to determine the odds ratio of each exposure prior to the diagnosis of PsA. “We actually examined all the patients with psoriasis to make sure they didn't have psoriatic arthritis,” she said.

Univariate analysis revealed that a history of infection requiring hospitalization was the strongest risk factor for the development of PsA, with an OR of 11.7. (Infective diarrhea carried an OR of 2.11.)

The second-highest risk factor was in the category of occupational exposure. A history of work involving cumulative lifting of at least 100 lb/hr carried an OR of 2.9, and pushing cumulative loads of at least 200 lb/hr carried an OR of 1.8.

And the third-highest risk factor was any injury requiring medical attention (OR, 2.43).

Multivariate analysis revealed that injuries requiring medical attention but excluding fracture and motor vehicle accident (OR, 2.3; P = .03), occupations requiring the lifting of heavy loads (OR, 2.7; P = .002), and severe infection requiring hospitalization (OR, 10.6; P = .03) were significantly associated with progression from psoriasis to PsA.

“For exposure to immunizations we found no risk, but another group [of investigators] has found that immunization was higher in those who got arthritis,” said Dr. Gladman.

“And psychological stress had no impact, although it has been reported that psoriatic patients without arthritis have a lot of stress; in fact, they may even have more because it turns out that patients with psoriasis and no arthritis actually have worse psoriasis.”

After the multifactorial analysis, smoking appeared to be associated with decreased risk, she added. Current smoking had an OR of 0.4 (P = .01), and past smoking had an OR of 0.5 (P = .04).

Dr. Gladman said that the findings are too preliminary to inform clinical recommendations at this time, but psoriasis patients should know that “if you have a job that requires a lot of lifting, you are more susceptible to getting psoriatic arthritis. Whether it's the only factor, we don't know, because there are also genetic factors involved. It's quite possible that in those people who are genetically predisposed, if they also do this work, they are more likely to get arthritis.” She said that the next step should be to look at genetic and environmental factors and see if they are independent or not.

Disclosures: Dr. Gladman declared no conflicts of interest.

Changes in the interphalangeal joints are shown in this x-ray of a patient with PsA in both hands.

Source © 2010 National Medical Slide Bank/Custom Medical Stock Photo, All Rights Reserved

My Take

Now We Need Prospective Trials

The potential impact of trauma on the development of psoriatic arthritis was first proposed over 50 years ago, when the observation of acryo-osteolysis in an injured digit was labeled “deep Koebner's effect.”

Two recent, retrospective, case-control studies analyzed the relationship between trauma and the onset of psoriatic arthritis. Corticosteroid use (in the first report) and immunization, moving house, and injury severe enough to require medical consultation (in the second report) were associated with incident PsA.

Dr. Gladman's study provides additional support for the association between trauma and incident PsA.

In this study, individuals with PsA were matched to psoriasis patients, and investigators found that injury requiring medical attention, heavy lifting, and severe infection were associated with the development of PsA.

Of course, many important questions remain to be addressed.

Could the retrospective designs of these case-control studies be strongly influenced by recall bias? This is possible but unlikely to account for these findings, given that both RA and psoriasis subjects have been used as controls.

A second question centers on the mechanisms that underlie this interesting association.

Two potential explanations have been suggested: the activation of proinflammatory molecules (such as nerve growth factor) that are produced in the psoriatic plaques, or high-level biomechanical stress to the synovial-entheseal complex, which triggers an innate immune response and subsequent inflammation.

Evidence amassed from several different sources supports the concept that trauma may be associated with the onset of PsA.

An adequately powered prospective study of psoriasis patients, with strict case definitions and appropriate control groups, will be required to adequately test the hypothesis and to understand the magnitude of a particular risk factor. Genetic risk factors could also be analyzed in such a study.

In the meantime, we await the details of Dr. Gladman's analysis, and we should make an effort to catalogue the events that are temporally related to the onset of inflammatory arthritis in our patients.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine at the University of Rochester (N.Y.). He reports having no relevant conflicts of interest.

MONTREAL — Occurance of injury, heavy lifting, severe infection, or other forms of trauma were associated with the progression of psoriasis to psoriatic arthritis in a study presented at the annual meeting of the Canadian Rheumatology Association.

“All we're talking about here is an association; we can't infer causation,” Dr. Dafna Gladman, the study's principal investigator, told Rheumatology News.

Previous, less rigorous studies have suggested the association between trauma and psoriatic arthritis (PsA), said Dr. Gladman, professor of medicine at the University of Toronto and deputy director of the Centre for Prognosis Studies in the Rheumatic Diseases in that city.

“This study supports that notion—that environmental factors are important—but we think genetic factors are also involved,” as well as immunologic factors, she said, explaining that at most, 30% of psoriasis patients go on to develop PsA.

Her study, which was presented as a poster at the meeting, compared 159 patients who had PsA with the same number of control patients who had psoriasis alone, in order to identify risk factors for progression to PsA. Men accounted for a similar percentage of both groups (46% in the PsA group and 44% in the controls).

The mean age of participants in each group was similar (45 years and 48 years, respectively) as was the mean duration of psoriasis (17.5 years and 18.5 years, respectively). The mean duration of PsA was 3 years.

A questionnaire was administered to all patients to assess their environmental exposure over the past 10 years, including occupational trauma, infection, immunization, smoking status and history, and psychological stress.

Univariate and multivariate logistic regression analysis was used to determine the odds ratio of each exposure prior to the diagnosis of PsA. “We actually examined all the patients with psoriasis to make sure they didn't have psoriatic arthritis,” she said.

Univariate analysis revealed that a history of infection requiring hospitalization was the strongest risk factor for the development of PsA, with an OR of 11.7. (Infective diarrhea carried an OR of 2.11.)

The second-highest risk factor was in the category of occupational exposure. A history of work involving cumulative lifting of at least 100 lb/hr carried an OR of 2.9, and pushing cumulative loads of at least 200 lb/hr carried an OR of 1.8.

And the third-highest risk factor was any injury requiring medical attention (OR, 2.43).

Multivariate analysis revealed that injuries requiring medical attention but excluding fracture and motor vehicle accident (OR, 2.3; P = .03), occupations requiring the lifting of heavy loads (OR, 2.7; P = .002), and severe infection requiring hospitalization (OR, 10.6; P = .03) were significantly associated with progression from psoriasis to PsA.

“For exposure to immunizations we found no risk, but another group [of investigators] has found that immunization was higher in those who got arthritis,” said Dr. Gladman.

“And psychological stress had no impact, although it has been reported that psoriatic patients without arthritis have a lot of stress; in fact, they may even have more because it turns out that patients with psoriasis and no arthritis actually have worse psoriasis.”

After the multifactorial analysis, smoking appeared to be associated with decreased risk, she added. Current smoking had an OR of 0.4 (P = .01), and past smoking had an OR of 0.5 (P = .04).

Dr. Gladman said that the findings are too preliminary to inform clinical recommendations at this time, but psoriasis patients should know that “if you have a job that requires a lot of lifting, you are more susceptible to getting psoriatic arthritis. Whether it's the only factor, we don't know, because there are also genetic factors involved. It's quite possible that in those people who are genetically predisposed, if they also do this work, they are more likely to get arthritis.” She said that the next step should be to look at genetic and environmental factors and see if they are independent or not.

Disclosures: Dr. Gladman declared no conflicts of interest.

Changes in the interphalangeal joints are shown in this x-ray of a patient with PsA in both hands.

Source © 2010 National Medical Slide Bank/Custom Medical Stock Photo, All Rights Reserved

My Take

Now We Need Prospective Trials

The potential impact of trauma on the development of psoriatic arthritis was first proposed over 50 years ago, when the observation of acryo-osteolysis in an injured digit was labeled “deep Koebner's effect.”

Two recent, retrospective, case-control studies analyzed the relationship between trauma and the onset of psoriatic arthritis. Corticosteroid use (in the first report) and immunization, moving house, and injury severe enough to require medical consultation (in the second report) were associated with incident PsA.

Dr. Gladman's study provides additional support for the association between trauma and incident PsA.

In this study, individuals with PsA were matched to psoriasis patients, and investigators found that injury requiring medical attention, heavy lifting, and severe infection were associated with the development of PsA.

Of course, many important questions remain to be addressed.

Could the retrospective designs of these case-control studies be strongly influenced by recall bias? This is possible but unlikely to account for these findings, given that both RA and psoriasis subjects have been used as controls.

A second question centers on the mechanisms that underlie this interesting association.

Two potential explanations have been suggested: the activation of proinflammatory molecules (such as nerve growth factor) that are produced in the psoriatic plaques, or high-level biomechanical stress to the synovial-entheseal complex, which triggers an innate immune response and subsequent inflammation.

Evidence amassed from several different sources supports the concept that trauma may be associated with the onset of PsA.

An adequately powered prospective study of psoriasis patients, with strict case definitions and appropriate control groups, will be required to adequately test the hypothesis and to understand the magnitude of a particular risk factor. Genetic risk factors could also be analyzed in such a study.

In the meantime, we await the details of Dr. Gladman's analysis, and we should make an effort to catalogue the events that are temporally related to the onset of inflammatory arthritis in our patients.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine at the University of Rochester (N.Y.). He reports having no relevant conflicts of interest.

SAN DIEGO — Much has been made recently of rheumatoid arthritis patients' substantially reduced life expectancy because of cardiovascular disease. Far less widely known is that they also have increased in-hospital mortality following acute respiratory failure.

A study of 22,121 adults in the U.S. Nationwide Inpatient Sample database who had an emergency hospitalization for acute respiratory failure from 2003 to 2006 showed that the 1,621 with comorbid rheumatoid arthritis or collagen vascular disease had an adjusted 21% increased risk of in-hospital mortality, Dr. David S. Kountz reported at the annual meeting of the American College of Chest Physicians.

The unadjusted in-hospital mortality rates in acute respiratory failure patients with or without rheumatoid arthritis or collagen vascular disease were closely similar: 25% in the rheumatologic group, and 24% in the 20,500 patients without such comorbidity. But the rheumatoid arthritis/collagen vascular disease group was younger, wealthier, and far more likely to be female.

After adjustment for these and other potential confounders, such as hospital teaching status, in a multivariate logistic regression analysis, the rheumatoid arthritis/collagen vascular disease group had a significantly greater in-hospital mortality risk, according to Dr. Kountz, senior vice president of medical and academic affairs at the Jersey Shore University Medical Center in Neptune, N.J.

Disclosures: Dr. Kountz having no conflicts of interest in connection with this study.

SAN DIEGO — Much has been made recently of rheumatoid arthritis patients' substantially reduced life expectancy because of cardiovascular disease. Far less widely known is that they also have increased in-hospital mortality following acute respiratory failure.

A study of 22,121 adults in the U.S. Nationwide Inpatient Sample database who had an emergency hospitalization for acute respiratory failure from 2003 to 2006 showed that the 1,621 with comorbid rheumatoid arthritis or collagen vascular disease had an adjusted 21% increased risk of in-hospital mortality, Dr. David S. Kountz reported at the annual meeting of the American College of Chest Physicians.

The unadjusted in-hospital mortality rates in acute respiratory failure patients with or without rheumatoid arthritis or collagen vascular disease were closely similar: 25% in the rheumatologic group, and 24% in the 20,500 patients without such comorbidity. But the rheumatoid arthritis/collagen vascular disease group was younger, wealthier, and far more likely to be female.

After adjustment for these and other potential confounders, such as hospital teaching status, in a multivariate logistic regression analysis, the rheumatoid arthritis/collagen vascular disease group had a significantly greater in-hospital mortality risk, according to Dr. Kountz, senior vice president of medical and academic affairs at the Jersey Shore University Medical Center in Neptune, N.J.

Disclosures: Dr. Kountz having no conflicts of interest in connection with this study.

SAN DIEGO — Much has been made recently of rheumatoid arthritis patients' substantially reduced life expectancy because of cardiovascular disease. Far less widely known is that they also have increased in-hospital mortality following acute respiratory failure.

A study of 22,121 adults in the U.S. Nationwide Inpatient Sample database who had an emergency hospitalization for acute respiratory failure from 2003 to 2006 showed that the 1,621 with comorbid rheumatoid arthritis or collagen vascular disease had an adjusted 21% increased risk of in-hospital mortality, Dr. David S. Kountz reported at the annual meeting of the American College of Chest Physicians.

The unadjusted in-hospital mortality rates in acute respiratory failure patients with or without rheumatoid arthritis or collagen vascular disease were closely similar: 25% in the rheumatologic group, and 24% in the 20,500 patients without such comorbidity. But the rheumatoid arthritis/collagen vascular disease group was younger, wealthier, and far more likely to be female.

After adjustment for these and other potential confounders, such as hospital teaching status, in a multivariate logistic regression analysis, the rheumatoid arthritis/collagen vascular disease group had a significantly greater in-hospital mortality risk, according to Dr. Kountz, senior vice president of medical and academic affairs at the Jersey Shore University Medical Center in Neptune, N.J.

Disclosures: Dr. Kountz having no conflicts of interest in connection with this study.