Psoriasis

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – New classification criteria for scleroderma presented at the annual European Congress of Rheumatology correctly identify more patients who could potentially be included in epidemiological studies and clinical trials than is possible with existing classification systems.

The new system is still a proposal and is under review by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR), according to Dr. Frank van den Hoogen, who is the director of the rheumatology center at Sint Maartenskliniek in Nijmegen and head of the department of rheumatology at Radboud University in Nijmegen, both in the Netherlands.

Sara Freeman/IMNG Medical Media

In a validation cohort, the ACR-EULAR criteria had a sensitivity of 91% and a specificity of 92% to correctly identify patients with systemic sclerosis. By comparison, the 1980 Preliminary ARA Criteria had a sensitivity of 75% and a specificity of 72%.

The whole process of developing the ACR-EULAR criteria has taken about 5 years, Dr. van den Hoogen explained in an interview. "The ARA criteria were not as sensitive as we wanted because they excluded some patients with limited disease and also patients with newly diagnosed disease," he added.

"The purpose of classification criteria is to include similar patients in research," Dr. van den Hoogen said. "Classification criteria are not synonymous with diagnostic criteria," he explained, "[they] are generally more standardized and less inclusive." This is because physicians will see patients with multiple symptoms and it would not be possible to include every symptom seen in routine practice in a set of classification criteria. Nevertheless, diagnostic criteria do tend to mirror classification criteria.

The process of determining which items to include was driven by both data and consensus. Delphi exercises and a nominal group technique were used to create a set of potential items for the classification of systemic sclerosis.

Several patient cases were then reviewed by leading scleroderma experts based in Europe and North America. The cases represented the full spectrum of systemic sclerosis, including those with a low and those with a high probability of having the disease. Experts ranked the importance of the symptoms exhibited by each of these cases, and a whittled down list with a scoring system was obtained. Systemic sclerosis was present if a score of 9 or more was achieved.

Skin thickening of the fingers of both hands extending past the metacarpophalangeal (MCP) joints was considered to be indicative of scleroderma, and was given a score of 9. Conversely, patients with skin involvement likely to be due to another scleroderma-like disorder or skin thickening sparing the fingers were not likely to have systemic sclerosis.

Other items included skin thickening of the fingers, with subitems of puffy fingers (score = 2) and whole finger skin thickening, distal to the MCP (4); fingertip lesions, with subitems of digital tip ulcers (2) and pitting scars (3), telangiectasia (2), abnormal nailfold capillaries (2); pulmonary arterial hypertension, interstitial lung disease, or both (2); Raynaud’s phenomenon (3); and the presence of any scleroderma-related autoantibodies (3).

The ability of these criteria to correctly identify patients with and without systemic sclerosis was then prospectively tested in a random sample of 200 individuals and further validated in a cohort of 405 individuals that included both early and prevalent cases of scleroderma and its mimics who had been collected from several European and North American scleroderma centers.

"The proposed ACR-EULAR criteria for the classification of systemic sclerosis should allow more patients to be classified correctly as systemic sclerosis," Dr. van den Hoogen said. This includes those with early (less than 3 years) scleroderma and the 20% of patients who have limited disease but who do not meet current classification criteria.

"New ACR [EULAR] criteria show increased sensitivity in comparison to the old [ARA] criteria," concurred Dr. Suzana Jordan of University Hospital Zurich. She presented findings on the use of the proposed system in 317 patients from the Zurich scleroderma cohort. This cohort mainly consists of patients with early or mild disease.

Applying the criteria to this Swiss patient population, Dr. Jordan noted that "75% of systemic sclerosis patients were correctly identified compared to just over half of all patients (51%) using the ARA criteria." Furthermore, "50% of early scleroderma patients who did not fulfill the old criteria met the new," she concluded.

Dr. van den Hoogen said that he had no disclosures, except that this work was funded jointly by EULAR and the ACR.

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

[email protected]

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

[email protected]

MADRID – The lessening of the signs and symptoms of psoriatic arthritis that occurs during the first 6 months of ustekinumab treatment persisted and improved further at the end of 1 year, with a favorable safety profile, according to 52-week data from the PSUMMIT II trial.

The sustained benefits in American College of Rheumatology (ACR) 20 responses and other efficacy endpoints were evident even in patients who had been treated previously with anti-tumor necrosis factor (anti-TNF) agents and among those who were anti-TNF naïve, although the benefits were greater in the latter group patients, according to Dr. Christopher T. Ritchlin, a professor in the department of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.). This includes beneficial effects on skin and enthesitis, Dr. Ritchlin said at the annual European Congress of Rheumatology.

The PSUMMIT II study is a follow-up to the PSUMMIT I study, the findings of which showed that ustekinumab, a human interleukin (IL)-12 and IL-23 antagonist, showed significant effectiveness in patients with psoriatic arthritis (PsA) who had not been exposed to anti-TNF drugs.

Ustekinumab is currently approved for treating moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy in the United States, or those who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies in Europe. In December 2012, the manufacturer, Janssen, announced that it had filed for further approval for ustekinumab in both the United States and Europe for the treatment of active disease.

The PSUMMIT II study enrolled 312 patients with active PsA who had five or more tender and five or more swollen joints, and a C-reactive protein level of 0.3 mg/dL or higher. Patients who had been treated previously with anti-TNF therapy (n = 180) and those naive to anti-TNF therapy (n = 132) were included and randomized to one of two doses of ustekinumab (45 mg or 90 mg) or placebo administered at week 0, 4, and 12. At 16 weeks, patients with less than a 5% improvement in tender and swollen joint counts on placebo were switched to active treatment, those on 45 mg ustekinumab had their dose upped to 90 mg, and those on 90 mg remained on that dose.

At 6 months, significantly more patients treated with ustekinumab than placebo achieved the primary endpoint of an ACR 20, and more patients on active treatment had an ACR 50, and at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75).

These results were sustained at 1 year, with 47%-48% of those on 45 mg and 90 mg, and 56% of those who switched from placebo to the 45-mg dose, achieving an ACR 20. In addition, 26%-29% achieved an ACR 50 (29% for those switched from placebo), and 13%-18% achieved an ACR 70 (15% for placebo). There were also improvements associated with treatment in HAQ-DI (Health Assessment Questionnaire-Disability Index) scores at week 52, according to Dr. Ritchlin. The mean change in HAQ-DI scores from baseline to week 52 were -0.21 for placebo, -0.20 for the 45-mg dose of ustekinumab, and -0.28 for the 90-mg dose.

Among those who had not been treated before with an anti-TNF agent, 59%-60% of those on ustekinumab (73% for those switched from placebo) achieved an ACR 20 at week 52, compared with 37%-41% of those who had taken an anti-TNF agent previously before being treated with ustekinumab (30% for placebo). Although responses among anti-TNF naive patients were superior, the responses among those who had been treated with these agents previously were still significantly improved, an indication that ustekinumab "offers an alternative for patients who cannot take or fail anti-TNF agents," Dr. Ritchlin said in the interview.

Treatment was "very effective" for skin symptoms and for enthesitis, he noted. Compared with baseline, dactylitis was improved by a median of 95% among those on the 45-mg dose, 91% among those on the 90-mg dose, and 100% in those who switched from placebo to the 45-mg dose of ustekinumab. Similar improvements in enthesitis were seen, with the highest improvement (60%) seen with the highest dose of ustekinumab. PASI scores at baseline ranged from 11 to 13 and improved by 56%-64% by follow-up at week 52.

In general, ustekinumab was well tolerated, with no deaths or cases of tuberculosis reported and with similar rates of adverse events and serious adverse events between the two doses (just under 6%). There were two malignancies: one breast cancer and one squamous cell carcinoma in two patients taking the 90-mg dose of ustekinumab, who had both been treated with anti-TNFs previously. The rate of serious infections was less than 1% among those treated with ustekinumab. Through 60 weeks of treatment, there were three major adverse cardiovascular events, all myocardial infarctions, in patients treated with ustekinumab. These patients all had multiple cardiovascular risk factors, Dr. Ritchlin said. They had also been exposed previously to anti-TNF treatment.

Radiographic data from the trial are expected and likely to be available by the end of the year for presentation at the annual American College of Rheumatology meeting.

Dr. Ritchlin disclosed having received grant and research support from Janssen. Four of the nine remaining authors are Janssen employees and shareholders of Johnson & Johnson, Janssen’s parent company. Ustekinumab is marketed as Stelara in the United States.

Sara Freeman contributed to this report.

[email protected]

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLORIDA – Central nervous system manifestations in patients with systemic lupus erythematosus should always trigger an evaluation for infection and other non–SLE-related etiologies, according to Dr. Julius Birnbaum.

That’s because between 33% and 50% of SLE patients will have a CNS syndrome that is not caused by SLE, Dr. Birnbaum said at the annual Congress of Clinical Rheumatology.

Infection is among the top causes of such syndromes.

"Because lupus patients are on immunosuppressive therapy, there always needs to be this paranoia for this lurking possibility of an infection," stressed Dr. Birnbaum of the departments of medicine and neurology at Johns Hopkins University, Baltimore.

The VITAMIN mnemonic device, similar to the VITAMINS mnemonic device he recommends for developing the differential diagnosis for peripheral nervous system manifestations, can also help with the differential diagnosis for CNS manifestation in neuropsychiatric SLE, he said.

"The stakes are a little bit higher now when we’re dealing with a lupus patient because we really want to make sure that we’re not overlooking a syndrome which would be exacerbated and not helped if we start immunosuppressive therapy," he said.

VITAMIN in this case represents:

• V – Vascular. In terms of stroke, it is important to think about septic emboli, subarachnoid hemorrhage from mycotic aneurysms, and septic thrombophlebitis.

• I – Infections. These should be classified by etiology (that is, bacterial, fungal, viral) and by anatomic region (is it parenchymal or meningeal, or does it have a vascular distribution, as in the case of septic emboli or thrombophlebitis?).

• T – Trauma. In SLE, this cause of CNS symptoms is similar to the general population.

• A – Autoimmune disorders. Always look for other autoimmune diseases as a cause.

• M – Metabolic disorders. These are uncommon as a cause of CNS symptoms, but may include hyperhomocysteinemia and B₁₂ deficiency.

• I – Iatrogenic complications. These are a major concern, and can include metabolic complications associated with steroid use or infections caused by immunosuppressive therapy.

• N – Neoplastic syndromes.

Dr. Birnbaum suggested using the VITAMIN mnemonic to get ideas for potentially useful diagnostic strategies, including routine serologic studies (such as an evaluation for uremia as a cause for encephalopathy or seizures); a work-up for infection (possibly including lumbar puncture); neuroimaging studies (such as CT to exclude a hemorrhage and MRI to further characterize space occupying lesions using specific sequences for strokes, for example); and diagnostic-specific strategies for distinct CNS disorders, such as EEG for the evaluation of seizures.

"Everything germinates from the patient’s symptoms ... you start with the symptoms, you do your neurological examination, and all of these tests that you’re going to order should be subordinated under a unifying strategy based on just the symptom and the examination," he said.

The next step, after reviewing the differential diagnosis, is to consider the specificity of a particular CNS syndrome for neuropsychiatric SLE, Dr. Birnbaum said.

Importantly, among the syndromes included in the American College of Rheumatology neuropsychiatric SLE nomenclature and case definition for the CNS neuropsychiatric SLE spectrum are several that have been shown – since the list was developed 15 years ago – to be nonspecific in that they are seen with similar frequency in non-SLE controls, he said.

These include headache, mood disorders, anxiety disorders, and mild cognitive impairment. In most cases, once "sinister causes" are ruled out using the VITAMIN mnemonic, these can be evaluated and treated as if the patient does not have SLE.

Only rarely are these nonspecific syndromes actually a manifestation of pathologic mechanism specific to SLE. In the right clinical context, examples may include an intractable "lupus headache" and depression or depression with unusual catatonic features, Dr. Birnbaum said.

"These are extraordinarily uncommon ... I want to emphasize that a neurological work-up can be standardized, but it is layered with some nuance, so there is no substitute for individual judgment," he said.

As for decisions regarding instituting symptomatic vs. immunosuppressive therapy, much of the decision will be based on the timing of the onset of symptoms relative to the onset of lupus.

"By and large, neurological symptoms that occur early into the onset of lupus tend to be more associated with lupus disease. Those neurological symptoms that occur later tend to be associated with damage," he said.

Seizures that occur in a young adult within 2 years of the onset of lupus, for example, tend to be associated with extraneurologic disease activity and increased organ activity. In this context, institution of immunosuppressive therapy for the extraneurologic disease should be considered.

Somewhat paradoxically, symptomatic therapy is usually needed only short term in cases with onset early in the course of lupus, because neurologic syndromes that occur early in disease onset are generally inflammatory and respond well, Dr. Birnbaum said.

Conversely, immunosuppressive therapy is usually not needed in cases of CNS symptom onset at 2 or more years after lupus onset, but these patients may require prolonged symptomatic therapy, he said, explaining that the symptoms often are due to permanent damage.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

DESTIN, FLA. – A simple mnemonic device can help to distinguish whether peripheral nervous system manifestations in patients with lupus and Sjögren’s syndrome are caused by the diseases themselves or by an alternate comorbidity, according to Dr. Julius Birnbaum.

The mnemonic device VITAMINS incorporates the spectrum of peripheral nervous system manifestations in lupus and Sjögren’s syndrome, and assists with the important task of fashioning a broad differential diagnosis and identifying the appropriate treatment, Dr. Birnbaum said at the Congress of Clinical Rheumatology.

Typically included in that spectrum of peripheral nervous system manifestations of lupus and Sjögren’s are a number of conditions that actually occur in less than 1% of patients, such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, plexopathy myasthenia gravis, and polyneuropathy without electrodiagnostic confirmation (except in cases of small-fiber neuropathy). Those conditions should therefore be considered as secondary and coincidental disease manifestations that can be managed as if the patient did not have lupus or Sjögren’s, said Dr. Birnbaum, associate professor of neurology at Johns Hopkins University, Baltimore.

Conversely, small-fiber neuropathies – painful sensory neuropathies that selectively or predominantly affect unmyelinated nociceptive fibers, are typically not included in that spectrum, but likely represent an underappreciated part of the spectrum of peripheral nervous system manifestations, he said. Small-fiber neuropathies are not detected by electrodiagnostic studies, which only test the integrity of larger-fiber myelinated nerves, he said.

In fact, in the context of supportive symptoms and physical examination, normal electromyography/nerve conduction velocity tests may actually support a diagnosis of small-fiber neuropathy. Furthermore, these neuropathies can cause unorthodox patterns of neuropathic pain, he said.

For example, in Sjögren’s syndrome, the patterns don’t always follow the typical “stocking and glove” distribution, and Sjögren’s patients with clinical features suggestive of small-fiber dysfunction may have normal skin biopsy studies.

Once these neuropathies are identified, the VITAMINS mnemonic can help in developing a differential. For small-fiber neuropathies, the mnemonic represents the following possible alternative causes:

 V – Vascular diagnoses, namely systemic vasculitides, but this is probably uncommon, according to Dr. Birnbaum.

 I – Infection, such as HIV and hepatitis C virus.

 T – Trauma, although this is very rare.

 A – Autoimmune/inflammatory disorders, especially celiac disease, sarcoidosis, and other rheumatic syndromes.

 M – Metabolic disorders. This typically means diabetes, but impaired glucose tolerance can also be the culprit, so a 2-hour glucose tolerance test is important. Other possible metabolic causes of small-fiber neuropathy are vitamin B₁₂ deficiency and hypothyroidism.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and cryoglobulinemia.

 N – Neoplastic disorders, particularly paraneoplastic disorders.

 S – Structural “mimics” such as syringomyelia and myeloradiculopathies.

Using this mnemonic, which “literally takes about 5 minutes,” is much easier than memorizing these numerous differential entities, he said.

A slightly altered version of the VITAMINS mnemonic can be used to identify the differential diagnoses for symmetric axonal polyneuropathies in lupus and Sjögren’s patients. In this case, the mnemonic represents the following alternative causes:

 V – Vasculitis. “Sometimes a very rapidly coalescing vasculitis can give the facsimile of a polyneuropathy,” Dr. Birnbaum said.

 I – Infection. As with small-fiber neuropathies, HIV and hepatitis C virus – even when not related to cryoglobulin – can cause symmetric axonal polyneuropathies.

 T – Trauma, although this is very rare.

 A – Autoimmune diseases, such as sarcoidosis.

 M – Metabolic disorders, namely diabetes and impaired glucose tolerance. A 2-hour glucose tolerance test should be ordered.

 I – Inflammatory disorders, including amyloidosis, paraproteinemia, and type 1 cryoglobulinemia.

 N – Neoplastic disorders, particularly lymphomatous or other infiltrative neuropathies (although these are usually associated with asymmetric symptoms), chemotherapy, and/or paraneoplastic syndromes.

 S – Structural causes. Compressive neuropathies are an example, although these are rare.

“Again you could use this mnemonic, and you’ll have the ability to really start honing in on pertinent and salient diagnoses, which might mimic a rheumatic disease,” Dr. Birnbaum said.

When it comes to treatment of these neuropathies and determining whether to use immunosuppressive therapies or symptomatic management, “it is useful to try to understand the relationship of a particular peripheral nervous system phenotype to disease activity versus disease damage,” he said.

Understanding differences in the characteristics of axonal neuropathy and mononeuritis multiplex can be helpful. For example, the prevalence of axonal polyneuropathies ranges from 1% to 10% in lupus and Sjögren’s, compared with a prevalence of less than 1% for mononeuritis multiplex. Also, lupus and Sjögren’s disease activity tends to be lower in the presence of axonal polyneuropathies and higher with mononeuritis multiplex.

Furthermore, disease-specific autoantibodies and immunological markers are not present in cases of axonal polyneuropathies, but Sjögren’s patients with mononeuritis multiplex may have cryoglobulinemia types II or III, high anti–rheumatoid factor, and low C4, Dr. Birnbaum said.

“By and large, most symmetric axonal polyneuropathies that you will see in lupus and Sjögren’s will tend to start distally, they will tend to start symmetrically. If they start in the feet, they usually stay restricted to the feet. If there is any migration it is very slow and occurs over years, if at all, and it usually tends to be much more sensory rather than motor,” he said.

Based on this more distal and sensory distribution, these patients can be managed, from the standpoint of their neuropathy, with symptomatic therapy, he added.

However, therapy in these patients needs to be “contextualized in the background of disease activity,” he said.

“Obviously, if the lupus patient has other extraneurological lupus disease activity, then you will institute immunosuppressive therapy, but just from the standpoint of symmetric axonal polyneuropathy, you usually do not have to,” he said.

In contrast, mononeuritis multiplex, much like antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, represents a jeopardized organ that is being targeted.

“You treat with immunosuppressive therapy for induction” in these cases, Dr. Birnbaum said.

Keep in mind, however, that even when immunosuppressive therapies are warranted, symptomatic management of neuropathic pain may still be necessary, he said.

Dr. Birnbaum reported having no disclosures.

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BIRMINGHAM, ENGLAND – Women with systemic lupus erythematous can be advised that azathioprine does not appear to adversely affect their children in the long term if they become pregnant.

In a U.K. cross-sectional survey that included children who were 17 years or younger and born to mothers with systemic lupus erythematosus (SLE), a univariate analysis showed that exposure to azathioprine did not increase the risk of major infections (odds ratio, 1.6; 95% confidence interval 0.8-3.2; P = .15) or developmental problems (OR, 1.22; 95% CI 0.44-3.42; P = .702).

Only the age of the child at assessment was associated with an increased risk of developmental problems, which were defined as attention–deficit/hyperactivity disorder, developmental delay, special needs, or special-education needs (OR, 1.15; P = .003).

The study provides "reassuring data to counsel women who are planning pregnancy in the future," Dr. Mary Gayed said the annual meeting of the British Society for Rheumatology.

"We know, from previous research, that certain immunosuppressant agents are used in pregnancy for lupus to prevent flare and to ensure optimum outcome for mother and child," Dr. Gayed said, but there have been few studies looking at long-term outcomes.

Dr. Gayed, a rheumatologist at Sandwell and West Birmingham (England) Hospitals, noted that the few, small studies that have been conducted have suggested a link between azathioprine use and an increased risk of infection, the presence of anticardiolipin antibodies, and developmental delay in the child.

To investigate the long-term consequences of SLE drugs on children’s outcomes further, Dr. Gayed and her associates performed a retrospective study involving eight English centers. The study involved a total of 287 children aged 17 years or younger who were born to 200 women who, before giving birth, had satisfied four or more SLE criteria as defined by the American College of Rheumatology.

The women had a mean age of 32 years when they gave birth to their first child and had a median disease duration of 7.1 years. The majority (65%) of women were white, with 15% of mothers being Asian, 10% Afro-Caribbean, and the remainder of "other" or unspecified ethnicity.

Maternal antibodies were detected in the children, including anti-Ro with or without lupus anticoagulant in 38%, any antiphospholipid antibody in 43%, lupus anticoagulant specifically in 33%, and anticardiolipin (IgG or IgM) in 23%.

Dr. Gayed reported that aspirin was the most commonly used drug during pregnancy and that 202 children had been exposed to it during their mothers’ pregnancy, followed by prednisolone exposure in 169 children, hydroxychloroquine in 152, azathioprine in 88, and heparin in 70. Another three children were exposed to cyclosporine, and one to mycophenolate.

In terms of obstetric outcomes, only 10% of mothers had experienced preeclampsia, of which 6% of cases were severe enough to warrant induction. Intrauterine growth restriction occurred in 11% of pregnancies (not known in a further 6%), with only 7% of cases being severe enough for the mother to be induced.

The mean gestation period was 36.3 weeks and most children were born by vaginal delivery (49%), with 39% born by cesarean section, and 11% with the aid of forceps. The mean birth weight of neonates was 2.7 kg.

The children were assessed at a mean age of 4.6 years. Infection requiring hospital assessment occurred in 40 (14%) of the 287 children studied. The age at which infections occurred reflected the age at which children were assessed in the study, with around half of all infections seen occurring in children less than 5 years of age.

Around 40% of infections were chest-related, Dr. Gayed reported: 17% were caused by pneumonia, 12% bronchiolitis, 5% upper respiratory tract infection, and 7% tonsillitis.

The age of children at assessment, the duration of pregnancy, and birth weight were also not associated with infection risk.

Dr. Gayed had no conflicts of interest. One coauthor disclosed receiving consultancy fees and honoraria from Genentech and Roche and an educational grant from Aspreva/Vifor.

[email protected]

BIRMINGHAM, ENGLAND – Women with systemic lupus erythematous can be advised that azathioprine does not appear to adversely affect their children in the long term if they become pregnant.

In a U.K. cross-sectional survey that included children who were 17 years or younger and born to mothers with systemic lupus erythematosus (SLE), a univariate analysis showed that exposure to azathioprine did not increase the risk of major infections (odds ratio, 1.6; 95% confidence interval 0.8-3.2; P = .15) or developmental problems (OR, 1.22; 95% CI 0.44-3.42; P = .702).

Only the age of the child at assessment was associated with an increased risk of developmental problems, which were defined as attention–deficit/hyperactivity disorder, developmental delay, special needs, or special-education needs (OR, 1.15; P = .003).

The study provides "reassuring data to counsel women who are planning pregnancy in the future," Dr. Mary Gayed said the annual meeting of the British Society for Rheumatology.

"We know, from previous research, that certain immunosuppressant agents are used in pregnancy for lupus to prevent flare and to ensure optimum outcome for mother and child," Dr. Gayed said, but there have been few studies looking at long-term outcomes.

Dr. Gayed, a rheumatologist at Sandwell and West Birmingham (England) Hospitals, noted that the few, small studies that have been conducted have suggested a link between azathioprine use and an increased risk of infection, the presence of anticardiolipin antibodies, and developmental delay in the child.

To investigate the long-term consequences of SLE drugs on children’s outcomes further, Dr. Gayed and her associates performed a retrospective study involving eight English centers. The study involved a total of 287 children aged 17 years or younger who were born to 200 women who, before giving birth, had satisfied four or more SLE criteria as defined by the American College of Rheumatology.

The women had a mean age of 32 years when they gave birth to their first child and had a median disease duration of 7.1 years. The majority (65%) of women were white, with 15% of mothers being Asian, 10% Afro-Caribbean, and the remainder of "other" or unspecified ethnicity.

Maternal antibodies were detected in the children, including anti-Ro with or without lupus anticoagulant in 38%, any antiphospholipid antibody in 43%, lupus anticoagulant specifically in 33%, and anticardiolipin (IgG or IgM) in 23%.

Dr. Gayed reported that aspirin was the most commonly used drug during pregnancy and that 202 children had been exposed to it during their mothers’ pregnancy, followed by prednisolone exposure in 169 children, hydroxychloroquine in 152, azathioprine in 88, and heparin in 70. Another three children were exposed to cyclosporine, and one to mycophenolate.

In terms of obstetric outcomes, only 10% of mothers had experienced preeclampsia, of which 6% of cases were severe enough to warrant induction. Intrauterine growth restriction occurred in 11% of pregnancies (not known in a further 6%), with only 7% of cases being severe enough for the mother to be induced.

The mean gestation period was 36.3 weeks and most children were born by vaginal delivery (49%), with 39% born by cesarean section, and 11% with the aid of forceps. The mean birth weight of neonates was 2.7 kg.

The children were assessed at a mean age of 4.6 years. Infection requiring hospital assessment occurred in 40 (14%) of the 287 children studied. The age at which infections occurred reflected the age at which children were assessed in the study, with around half of all infections seen occurring in children less than 5 years of age.

Around 40% of infections were chest-related, Dr. Gayed reported: 17% were caused by pneumonia, 12% bronchiolitis, 5% upper respiratory tract infection, and 7% tonsillitis.

The age of children at assessment, the duration of pregnancy, and birth weight were also not associated with infection risk.

Dr. Gayed had no conflicts of interest. One coauthor disclosed receiving consultancy fees and honoraria from Genentech and Roche and an educational grant from Aspreva/Vifor.

[email protected]

BIRMINGHAM, ENGLAND – Women with systemic lupus erythematous can be advised that azathioprine does not appear to adversely affect their children in the long term if they become pregnant.

In a U.K. cross-sectional survey that included children who were 17 years or younger and born to mothers with systemic lupus erythematosus (SLE), a univariate analysis showed that exposure to azathioprine did not increase the risk of major infections (odds ratio, 1.6; 95% confidence interval 0.8-3.2; P = .15) or developmental problems (OR, 1.22; 95% CI 0.44-3.42; P = .702).

Only the age of the child at assessment was associated with an increased risk of developmental problems, which were defined as attention–deficit/hyperactivity disorder, developmental delay, special needs, or special-education needs (OR, 1.15; P = .003).

The study provides "reassuring data to counsel women who are planning pregnancy in the future," Dr. Mary Gayed said the annual meeting of the British Society for Rheumatology.

"We know, from previous research, that certain immunosuppressant agents are used in pregnancy for lupus to prevent flare and to ensure optimum outcome for mother and child," Dr. Gayed said, but there have been few studies looking at long-term outcomes.

Dr. Gayed, a rheumatologist at Sandwell and West Birmingham (England) Hospitals, noted that the few, small studies that have been conducted have suggested a link between azathioprine use and an increased risk of infection, the presence of anticardiolipin antibodies, and developmental delay in the child.

To investigate the long-term consequences of SLE drugs on children’s outcomes further, Dr. Gayed and her associates performed a retrospective study involving eight English centers. The study involved a total of 287 children aged 17 years or younger who were born to 200 women who, before giving birth, had satisfied four or more SLE criteria as defined by the American College of Rheumatology.

The women had a mean age of 32 years when they gave birth to their first child and had a median disease duration of 7.1 years. The majority (65%) of women were white, with 15% of mothers being Asian, 10% Afro-Caribbean, and the remainder of "other" or unspecified ethnicity.

Maternal antibodies were detected in the children, including anti-Ro with or without lupus anticoagulant in 38%, any antiphospholipid antibody in 43%, lupus anticoagulant specifically in 33%, and anticardiolipin (IgG or IgM) in 23%.

Dr. Gayed reported that aspirin was the most commonly used drug during pregnancy and that 202 children had been exposed to it during their mothers’ pregnancy, followed by prednisolone exposure in 169 children, hydroxychloroquine in 152, azathioprine in 88, and heparin in 70. Another three children were exposed to cyclosporine, and one to mycophenolate.

In terms of obstetric outcomes, only 10% of mothers had experienced preeclampsia, of which 6% of cases were severe enough to warrant induction. Intrauterine growth restriction occurred in 11% of pregnancies (not known in a further 6%), with only 7% of cases being severe enough for the mother to be induced.

The mean gestation period was 36.3 weeks and most children were born by vaginal delivery (49%), with 39% born by cesarean section, and 11% with the aid of forceps. The mean birth weight of neonates was 2.7 kg.

The children were assessed at a mean age of 4.6 years. Infection requiring hospital assessment occurred in 40 (14%) of the 287 children studied. The age at which infections occurred reflected the age at which children were assessed in the study, with around half of all infections seen occurring in children less than 5 years of age.

Around 40% of infections were chest-related, Dr. Gayed reported: 17% were caused by pneumonia, 12% bronchiolitis, 5% upper respiratory tract infection, and 7% tonsillitis.

The age of children at assessment, the duration of pregnancy, and birth weight were also not associated with infection risk.

Dr. Gayed had no conflicts of interest. One coauthor disclosed receiving consultancy fees and honoraria from Genentech and Roche and an educational grant from Aspreva/Vifor.

[email protected]