ACR Winter Rheumatology Symposium 2011

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Treatment of macrophage activation syndrome with a combination of high-dose corticosteroids and cyclosporine is quite effective in the great majority of cases if started sufficiently early; it’s what to do for the others where the controversy arises.

One reasonable option is to utilize the International Histiocyte Society treatment protocol for hemophagocytic lymphohistiocytosis, a hematology/oncology disorder bearing clinical similarities to macrophage activation syndrome (MAS). This protocol entails supplementing corticosteroids and cyclosporine with etoposide (VP-16), which is a mitotic inhibitor and antineoplastic agent used in treating a variety of cancers. Etoposide is employed to induce apoptosis of activated phagocytic macrophages and other immune cells, Dr. Alexei A. Grom said at a symposium sponsored by the American College of Rheumatology.

But while etoposide is a reasonable next step, the drug’s numerous short- and long-term side effects – including severe myelosuppression leading to fatal sepsis – have caused many physicians to look for alternatives. Among the more promising are antithymocyte globulin and rituximab, said Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Antithymocyte globulin depletes T cells, including CD8 cells, and monocytes. Numerous case reports describe successful use of this agent in treating MAS.

The rationale for using rituximab, a potent depleter of B cells, applies to patients with Epstein-Barr virus–induced MAS. Because of the immune dysfunction present in MAS, these patients develop persistent viral infection harbored chiefly by B cells. Dr. Grom has used rituximab successfully in patients with Epstein-Barr virus–triggered MAS, and he suspects that this approach may also be very effective in the setting of MAS associated with systemic lupus erythematosus.

The increased level of tumor necrosis factor present in MAS has prompted numerous attempts to use etanercept and other anti-TNF biologics. Results have been largely disappointing.

"Personally, I think we should stay away from TNF-alpha antagonists in MAS," the pediatric rheumatologist said.

The efficacy of interleukin-1 and -6 inhibiting agents in systemic juvenile idiopathic arthritis (SJIA) makes them appealing agents for the treatment of MAS, because MAS episodes are often triggered by flares of SJIA. However, case reports involving the interleukin-1 inhibitor anakinra have yielded mixed results, and to date there is very little experience with interleukin-6 inhibition in MAS.

First-line treatment of MAS by Dr. Grom and his Cincinnati colleagues begins with high-dose steroids, typically 3-5 days of intravenous methylprednisolone pulses at 30 mg/kg/day before dropping down to 2-3 mg/kg in two or three divided doses. Cyclosporine is dosed at 2-5 mg/kg in two divided doses, usually given intravenously.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – The pendulum appears to be swinging away from the broad definition of neuropsychiatric systemic lupus erythematosus advocated by the American College of Rheumatology in a landmark 1999 report in favor of a much more restrictive set of manifestations, according to Dr. W. Joseph McCune.

The ACR list of 19 neuropsychiatric syndromes attributable to SLE includes headache, mood disorders, cognitive dysfunction, and anxiety disorders (Arthritis Rheum. 1999;42:599-608). The problem is that these features are quite common among individuals without SLE, and attributing them to lupus activity can result in overestimation of the prevalence of neuropsychiatric SLE and overtreatment of lupus, he said at the meeting.

The ACR case definitions have resulted in a great expansion of the perceived incidence and prevalence of neuropsychiatric lupus. But last year, a European League Against Rheumatism consensus statement on neuropsychiatric SLE suggested that the sweeping ACR conception goes too far, noted Dr. McCune, professor of internal medicine at the University of Michigan, Ann Arbor.

The EULAR report concluded that excluding headache, mood disorders, anxiety disorders, mild cognitive dysfunction, and polyneuropathy without electromyographic confirmation from the ACR list of manifestations of neuropsychiatric SLE would reduce the reported frequency of neuropsychiatric lupus by half while doubling the specificity of the ACR nomenclature from 46% to 93% (Ann. Rheum. Dis. 2010;69:2074-82).

The EULAR report identified three risk factors consistently associated with roughly a fivefold increased likelihood that a neuropsychiatric symptom is actually due to the patient’s lupus rather than to a secondary cause such as comorbid hypertension, infection, or cardiac vegetations. These risk factors are generalized SLE activity; a moderate to high titer of antiphospholipid antibodies, which particularly predispose to lupus as the primary cause in cases involving seizures, cerebrovascular disease, or chorea; and previous neuropsychiatric SLE manifestations, which greatly increase the likelihood that seizures or cognitive dysfunction in a lupus patient are actually due to the SLE.

Another key point made in the EULAR consensus statement was that 50%-60% of neuropsychiatric SLE events occur at the onset of lupus or within the first year afterward.

"That means one has to be alert to the possibility that someone who presents with an incompletely developed syndrome may ultimately turn out to have lupus," Dr. McCune observed.

The impact of the ACR’s broad list of manifestations of neuropsychiatric lupus was apparent in a recent meta-analysis of 10 studies of the prevalence of neuropsychiatric SLE conducted since the ACR report was published. The average prevalence of neuropsychiatric syndromes as defined by the ACR was 56% among lupus patients, and in two studies it exceeded 90%. The three most common neuropsychiatric syndromes in the meta-analysis were headache in 28% of SLE patients, mood disorders in 21%, and cognitive dysfunction in 20% (Semin. Arthritis Rheum. 2010 Oct. 20 [doi:10.1016/j.semarthrit.2010.08.001]).

Dr. McCune noted that when the Michigan Lupus Epidemiology and Surveillance Program (MiLES) was established close to a decade ago, investigators chose to track only a subset of the 19 neuropsychiatric syndromes on the ACR list: seizure disorders, cerebrovascular accidents, psychosis, mononeuropathy, aseptic meningitis, acute transverse myelitis, chorea, and cranial neuropathy.

MiLES is an ongoing Centers for Disease Control and Prevention–sponsored population-based survey of lupus in Wayne and Washtenaw counties. Together the two counties have a population of about 2.3 million that’s 55% white and 38% African American. To date, in an interim analysis, 2,372 residents have been identified who fulfill ACR requirements for the diagnosis of SLE. That’s an SLE prevalence of roughly 1 in 1,000 individuals, a considerably higher figure than the usually cited estimates of 1 in 500 among African American women and 1 per 2,000 white women, with much lower rates in men.

Among SLE patients identified in MiLES, 18% had at least one neuropsychiatric manifestation attributed by investigators to their lupus. Several intriguing sex-based differences have been found. For instance, the prevalence of neuropsychiatric SLE was significantly higher among men with SLE, at 26%, compared with 17.6% in women, even though men had a shorter average disease duration. This finding is consistent with the hypothesis that men tend to have more severe lupus even though they have a much lower incidence of the disease than women.

Seizures were the most common neuropsychiatric manifestation in both men and women with lupus, but were roughly twice as common among the men. Aseptic meningitis was also significantly more prevalent among male lupus patients.

African American women with SLE had significantly more seizures, cerebrovascular accidents, and psychosis than did white women. Among men, in contrast, there were no significant racial differences in any of the neurologic features being tracked, Dr. McCune said.

He said he had no relevant financial disclosures.

SNOWMASS, COLO. – Macrophage activation syndrome is a challenging diagnosis whose most useful clues are to be found in the laboratory report.

Suspect the life-threatening diagnosis of macrophage activation syndrome (MAS) in a patient with virtually any form of active rheumatologic disease who becomes acutely ill with a sharp drop in both erythrocyte sedimentation rate and platelet count in the presence of a persistently high C-reactive protein and escalating levels of serum D-dimers, urged Dr. Alexei A. Grom.

Another suggestive laboratory feature is marked hyperferritinemia. Patients with MAS often have a serum ferritin level in excess of 10,000 ng/mL, Dr. Grom said at a symposium sponsored by the American College of Rheumatology.

Moreover, while normally 60%-80% of serum ferritin is glycosylated, in MAS it’s typically less than 20%. This makes measurement of serum glycosylated ferritin a useful diagnostic tool, noted Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Assessment of serum levels of soluble CD163 and soluble interleukin-2-receptor-alpha chains can also help pin down the diagnosis. They are strikingly elevated in MAS, and not in many other conditions. Extreme hypertriglyceridemia is another characteristic feature.

The central feature of MAS, he continued, is uncontrolled expansion of cytotoxic CD8 cells secreting cytokines that stimulate macrophages to exhibit hemophagocytic activity.

Indeed, hemophagocytic activity on the part of highly activated macrophages is the hallmark of MAS. Identification of hemophagocytic macrophages in the bone marrow confirms the diagnosis. Unfortunately, often this finding is not present early in the course of the disease.

This macrophage hemophagocytosis explains the extreme hyperferritinemia seen in MAS. Free hemoglobin is released as erythrocytes are phagocytized. This creates a need to boost ferritin production in order to sequestrate the free iron, he explained.

Three cardinal features of the massive systemic inflammatory response that defines MAS are liver dysfunction, cytopenias, and coagulopathy consistent with disseminated intravascular coagulation. However, like hemophagocytic macrophages in the bone marrow, these features often are not of much help in making an early diagnosis. Overt cytopenia is seen only in the late stages of MAS.

Abnormal liver function tests and laboratory evidence of coagulopathy can also occur in a flare of systemic juvenile idiopathic arthritis – and since 80% of pediatric MAS occurs in patients with SJIA, hepatic dysfunction and coagulopathy are not useful in making the distinction.

The clinical presentation of MAS includes persistent fever, impressively enlarged lymph nodes, prominent hepatosplenomegaly, and a hemorrhagic rash featuring bruising, then purpura, followed by mucosal bleeding. Many patients also develop mental status changes and/or seizures. These clinical features can be viewed as largely a consequence of a cytokine storm involving increased interferon-gamma, granulocyte macrophage colony–stimulating factor, tumor necrosis factor-alpha, and interleukin-1, -6, and -18.

No trigger is identifiable in the majority of cases of MAS. When a trigger is found, it is most commonly an infection with Epstein-Barr virus or cytomegalovirus.

MAS has a 10%-20% mortality. The death rate is declining in pediatric patients because of increasing awareness of the syndrome and consequent earlier diagnosis and initiation of treatment.

"I think that in adult rheumatology this condition is still relatively unrecognized. My adult rheumatology colleagues in Cincinnati believe that many of these patients end up with a diagnosis of culture-negative sepsis," Dr. Grom said.

It’s crucial to understand that roughly one-third of patients with MAC will experience recurrent episodes. For this reason, Dr. Grom provides patients with a letter explaining their condition in the event they should have a recurrence while out of town, necessitating a visit to an emergency department where physicians may be MAC inexperienced.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Macrophage activation syndrome is a challenging diagnosis whose most useful clues are to be found in the laboratory report.

Suspect the life-threatening diagnosis of macrophage activation syndrome (MAS) in a patient with virtually any form of active rheumatologic disease who becomes acutely ill with a sharp drop in both erythrocyte sedimentation rate and platelet count in the presence of a persistently high C-reactive protein and escalating levels of serum D-dimers, urged Dr. Alexei A. Grom.

Another suggestive laboratory feature is marked hyperferritinemia. Patients with MAS often have a serum ferritin level in excess of 10,000 ng/mL, Dr. Grom said at a symposium sponsored by the American College of Rheumatology.

Moreover, while normally 60%-80% of serum ferritin is glycosylated, in MAS it’s typically less than 20%. This makes measurement of serum glycosylated ferritin a useful diagnostic tool, noted Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Assessment of serum levels of soluble CD163 and soluble interleukin-2-receptor-alpha chains can also help pin down the diagnosis. They are strikingly elevated in MAS, and not in many other conditions. Extreme hypertriglyceridemia is another characteristic feature.

The central feature of MAS, he continued, is uncontrolled expansion of cytotoxic CD8 cells secreting cytokines that stimulate macrophages to exhibit hemophagocytic activity.

Indeed, hemophagocytic activity on the part of highly activated macrophages is the hallmark of MAS. Identification of hemophagocytic macrophages in the bone marrow confirms the diagnosis. Unfortunately, often this finding is not present early in the course of the disease.

This macrophage hemophagocytosis explains the extreme hyperferritinemia seen in MAS. Free hemoglobin is released as erythrocytes are phagocytized. This creates a need to boost ferritin production in order to sequestrate the free iron, he explained.

Three cardinal features of the massive systemic inflammatory response that defines MAS are liver dysfunction, cytopenias, and coagulopathy consistent with disseminated intravascular coagulation. However, like hemophagocytic macrophages in the bone marrow, these features often are not of much help in making an early diagnosis. Overt cytopenia is seen only in the late stages of MAS.

Abnormal liver function tests and laboratory evidence of coagulopathy can also occur in a flare of systemic juvenile idiopathic arthritis – and since 80% of pediatric MAS occurs in patients with SJIA, hepatic dysfunction and coagulopathy are not useful in making the distinction.

The clinical presentation of MAS includes persistent fever, impressively enlarged lymph nodes, prominent hepatosplenomegaly, and a hemorrhagic rash featuring bruising, then purpura, followed by mucosal bleeding. Many patients also develop mental status changes and/or seizures. These clinical features can be viewed as largely a consequence of a cytokine storm involving increased interferon-gamma, granulocyte macrophage colony–stimulating factor, tumor necrosis factor-alpha, and interleukin-1, -6, and -18.

No trigger is identifiable in the majority of cases of MAS. When a trigger is found, it is most commonly an infection with Epstein-Barr virus or cytomegalovirus.

MAS has a 10%-20% mortality. The death rate is declining in pediatric patients because of increasing awareness of the syndrome and consequent earlier diagnosis and initiation of treatment.

"I think that in adult rheumatology this condition is still relatively unrecognized. My adult rheumatology colleagues in Cincinnati believe that many of these patients end up with a diagnosis of culture-negative sepsis," Dr. Grom said.

It’s crucial to understand that roughly one-third of patients with MAC will experience recurrent episodes. For this reason, Dr. Grom provides patients with a letter explaining their condition in the event they should have a recurrence while out of town, necessitating a visit to an emergency department where physicians may be MAC inexperienced.

Dr. Grom declared having no relevant financial interests.

SNOWMASS, COLO. – Macrophage activation syndrome is a challenging diagnosis whose most useful clues are to be found in the laboratory report.

Suspect the life-threatening diagnosis of macrophage activation syndrome (MAS) in a patient with virtually any form of active rheumatologic disease who becomes acutely ill with a sharp drop in both erythrocyte sedimentation rate and platelet count in the presence of a persistently high C-reactive protein and escalating levels of serum D-dimers, urged Dr. Alexei A. Grom.

Another suggestive laboratory feature is marked hyperferritinemia. Patients with MAS often have a serum ferritin level in excess of 10,000 ng/mL, Dr. Grom said at a symposium sponsored by the American College of Rheumatology.

Moreover, while normally 60%-80% of serum ferritin is glycosylated, in MAS it’s typically less than 20%. This makes measurement of serum glycosylated ferritin a useful diagnostic tool, noted Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.

Assessment of serum levels of soluble CD163 and soluble interleukin-2-receptor-alpha chains can also help pin down the diagnosis. They are strikingly elevated in MAS, and not in many other conditions. Extreme hypertriglyceridemia is another characteristic feature.

The central feature of MAS, he continued, is uncontrolled expansion of cytotoxic CD8 cells secreting cytokines that stimulate macrophages to exhibit hemophagocytic activity.

Indeed, hemophagocytic activity on the part of highly activated macrophages is the hallmark of MAS. Identification of hemophagocytic macrophages in the bone marrow confirms the diagnosis. Unfortunately, often this finding is not present early in the course of the disease.

This macrophage hemophagocytosis explains the extreme hyperferritinemia seen in MAS. Free hemoglobin is released as erythrocytes are phagocytized. This creates a need to boost ferritin production in order to sequestrate the free iron, he explained.

Three cardinal features of the massive systemic inflammatory response that defines MAS are liver dysfunction, cytopenias, and coagulopathy consistent with disseminated intravascular coagulation. However, like hemophagocytic macrophages in the bone marrow, these features often are not of much help in making an early diagnosis. Overt cytopenia is seen only in the late stages of MAS.

Abnormal liver function tests and laboratory evidence of coagulopathy can also occur in a flare of systemic juvenile idiopathic arthritis – and since 80% of pediatric MAS occurs in patients with SJIA, hepatic dysfunction and coagulopathy are not useful in making the distinction.

The clinical presentation of MAS includes persistent fever, impressively enlarged lymph nodes, prominent hepatosplenomegaly, and a hemorrhagic rash featuring bruising, then purpura, followed by mucosal bleeding. Many patients also develop mental status changes and/or seizures. These clinical features can be viewed as largely a consequence of a cytokine storm involving increased interferon-gamma, granulocyte macrophage colony–stimulating factor, tumor necrosis factor-alpha, and interleukin-1, -6, and -18.

No trigger is identifiable in the majority of cases of MAS. When a trigger is found, it is most commonly an infection with Epstein-Barr virus or cytomegalovirus.

MAS has a 10%-20% mortality. The death rate is declining in pediatric patients because of increasing awareness of the syndrome and consequent earlier diagnosis and initiation of treatment.

"I think that in adult rheumatology this condition is still relatively unrecognized. My adult rheumatology colleagues in Cincinnati believe that many of these patients end up with a diagnosis of culture-negative sepsis," Dr. Grom said.

It’s crucial to understand that roughly one-third of patients with MAC will experience recurrent episodes. For this reason, Dr. Grom provides patients with a letter explaining their condition in the event they should have a recurrence while out of town, necessitating a visit to an emergency department where physicians may be MAC inexperienced.

Dr. Grom declared having no relevant financial interests.