Primary Care/Internal Medicine

The levels of evidence supporting the recommendations (A-C) are defined at the end of the "Major Recommendations" field.

Recommendations for the Use of Disease-Modifying Antirheumatic Drugs (DMARDs) and Biologic Agents in Patients Who Qualify for Treatment of Rheumatoid Arthritis (RA)

This 2012 American College of Rheumatology (ACR) recommendations update incorporates the evidence from systematic literature review synthesis and recommendations from 2008 and rates updated and new clinical scenarios regarding the use of DMARDs and biologic agents for the treatment of RA. Terms used in the recommendations are defined in Table 2 of the original guideline document. The 2012 recommendations are listed in the 4 sections below and in the following order:

1. Indications for and switching DMARDs and biologic agents: early RA (indications, see Figure 1 in the original guideline document) followed by established RA (indications and switching, see Figure 2 in the original guideline document), along with details of the level of evidence supporting these recommendations (see Supplementary Appendix 7, available in the online version at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 
   
   )
2. Use of biologic agents in patients with hepatitis, malignancy, or congestive heart failure (CHF) who qualify for RA management (see Table 4 in the original guideline document)
3. Screening for tuberculosis (TB) in patients starting or currently receiving biologic agents as part of their RA therapy (see Figure 3 in the original guideline document)
4. Vaccination in patients starting or currently receiving DMARDs or biologic agents as part of their RA therapy (see Table 5 in the original guideline document)

The recommendations in the text below and in Tables 4 and 5 in the original guideline document represent the results of the 2012 update only, whereas Figures 1–3 in the original guideline document also incorporate some of the 2008 ACR RA recommendations that did not change. Areas of uncertainty by the panel (that did not lead to recommendations) are noted in Supplementary Appendix 8 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

1. Indications for Starting, Resuming, Adding, or Switching DMARDs or Biologic Agents

   The panel first describes a recommendation targeting remission or low disease activity in RA (section 1A). This is followed by recommendations for DMARD or biologic agent use in early RA (section 1B). Next, the panel provides recommendations for initiating and switching between DMARDs and biologic agents in established RA (section 1C).

   1A. Target Low Disease Activity or Remission

   The panel recommends targeting either low disease activity (see Table 3 in the original guideline document) or remission (see Table 2 in the original guideline document) in all patients with early RA (see Figure 1 in the original guideline document; level of evidence C) and established RA (see Figure 2 in the original guideline document; level of evidence C) receiving any DMARD or biologic agent.

   1B. Early RA (Disease Duration <6 Months)

   In patients with early RA, the panel recommends the use of DMARD monotherapy both for low disease activity and for moderate or high disease activity with the absence of poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C) (details are shown in Supplementary Appendix 7, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

   
   ).

   In patients with early RA, the panel recommends the use of DMARD combination therapy (including double and triple therapy) in patients with moderate or high disease activity plus poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C).

   In patients with early RA, the panel also recommends the use of an anti-tumor necrosis factor (anti-TNF) biologic with or without methotrexate in patients who have high disease activity with poor prognostic features (see Figure 1 in the original guideline document; level of evidence A and B). Infliximab is the only exception and the recommendation is to use it in combination with methotrexate, but not as monotherapy.

   1C. Established RA (Disease Duration ≥6 Months or Meeting the 1987 ACR RA Classification Criteria)

   The remainder of panel recommendations regarding indications for DMARDs and biologic agents are for patients with established RA. The 3 subsections below define recommendations for initiating and switching therapies in established RA (see Figure 2 in the original guideline document). Where the prognosis is not mentioned, the recommendation to use/switch to a DMARD or a biologic agent applies to all patients, regardless of prognostic features.

   Initiating and Switching Among DMARDs

   If after 3 months of DMARD monotherapy (in patients without poor prognostic features), a patient deteriorates from low to moderate/high disease activity, then methotrexate, hydroxychloroquine, or leflunomide should be added (see rectangle A of Figure 2 in the original guideline document; level of evidence A and B).

   If after 3 months of methotrexate or methotrexate/DMARD combination, a patient still has moderate or high disease activity, then add another non-methotrexate DMARD or switch to a different non-methotrexate DMARD (see rectangle B of Figure 2 in the original guideline document; level of evidence B and C).

   Switching from DMARDs to Biologic Agents

   If a patient has moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy, as an alternative to the DMARD recommendation just noted above, the panel recommends adding or switching to an anti-TNF biologic, abatacept, or rituximab (see rectangles C and D of Figure 2 in the original guideline document; level of evidence A–C).

   If after 3 months of intensified DMARD combination therapy or after a second DMARD, a patient still has moderate or high disease activity, add or switch to an anti-TNF biologic (see rectangle C of Figure 2 in the original guideline document; level of evidence C).

   Switching Among Biologic Agents Due to Lack of Benefit or Loss of Benefit

   If a patient still has moderate or high disease activity after 3 months of anti-TNF biologic therapy and this is due to a lack or loss of benefit, switching to another anti-TNF biologic or a non-TNF biologic is recommended (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient still has moderate or high disease activity after 6 months of a non-TNF biologic and the failure is due to a lack or loss of benefit, switch to another non-TNF biologic or an anti-TNF biologic (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C). An assessment period of 6 months was chosen rather than 3 months, due to the anticipation that a longer time may be required for efficacy of a non-TNF biologic.

   Switching Among Biologic Agents Due to Harms/Adverse Events

   If a patient has high disease activity after failing an anti-TNF biologic because of a serious adverse event, switch to a non-TNF biologic (see rectangle E of Figure 2 in the original guideline document; level of evidence C).

   If a patient has moderate or high disease activity after failing an anti-TNF biologic because of a nonserious adverse event, switch to another anti-TNF biologic or a non-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient has moderate or high disease activity after failing a non-TNF biologic because of an adverse event (serious or nonserious), switch to another non-TNF biologic or an anti-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence C).

2. Use of Biologic Agents in RA Patients With Hepatitis, Malignancy, or Chronic Heart Failure (CHF), Qualifying for More Aggressive Treatment (level of evidence C for all recommendations)

   Hepatitis B or C

   The panel recommends that etanercept could potentially be used in RA patients with hepatitis C requiring RA treatment (see Table 4 in the original guideline document).

   The panel also recommends not using biologic agents in RA patients with untreated chronic hepatitis B (disease not treated due to contraindications to treatment or intolerable adverse events) and in RA patients with treated chronic hepatitis B with Child-Pugh class B and higher (see Table 4 in the original guideline document; for details of Child-Pugh classification, see Table 2 in the original guideline document). The panel did not make recommendations regarding the use of any biologic agent for treatment in RA patients with a history of hepatitis B and a positive hepatitis B core antibody.

   Malignancies

   For patients who have been treated for solid malignancies more than 5 years ago or who have been treated for nonmelanoma skin cancer more than 5 years ago, the panel recommends starting or resuming any biologic agent if those patients would otherwise qualify for this RA management strategy (see Table 4 in the original guideline document).

   The panel only recommends starting or resuming rituximab in RA patients with: 1) a previously treated solid malignancy within the last 5 years, 2) a previously treated nonmelanoma skin cancer within the last 5 years, 3) a previously treated melanoma skin cancer, or 4) a previously treated lymphoproliferative malignancy. Little is known about the effects of biologic therapy in patients with a history of a solid cancer within the past 5 years owing to the exclusion of such patients from participation in clinical trials and the lack of studies examining the risk of recurrent cancer in this subgroup of patients.

   CHF

   The panel recommends not using an anti-TNF biologic in RA patients with CHF that is New York Heart Association (NYHA) class III or IV and who have an ejection fraction of 50% or less (see Table 4 in the original guideline document).

3. TB Screening for Biologic Agents (level of evidence C for all recommendations except for initiation of biologic agents in patients being treated for latent TB infection [LTBI], where the level of evidence is B)

   The panel recommends screening to identify LTBI in all RA patients being considered for therapy with biologic agents, regardless of the presence of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends that clinicians assess the patient's medical history to identify risk factors for TB (specified by the Centers for Disease Control and Prevention [CDC]) (see Table 2 in the original guideline document).

   The panel recommends the tuberculin skin test (TST) or interferon-gamma–release assays (IGRAs) as the initial test in all RA patients starting biologic agents, regardless of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends the use of the IGRA over the TST in patients who had previously received a bacillus Calmette-Guerin (BCG) vaccination, due to the high false-positive test rates for TST (see Figure 3 in the original guideline document).

   The panel recommends that RA patients with a positive initial or repeat TST or IGRA should have a chest radiograph and, if suggestive of active TB, a subsequent sputum examination to check for the presence of active TB (see diamonds B and C of Figure 3 in the original guideline document). RA patients with a negative screening TST or IGRA may not need further evaluation in the absence of risk factors and/or clinical suspicion for TB. Since patients with RA may have false-negative TST or IGRA results due to immunosuppression, a negative TST or IGRA should not be interpreted as excluding the possibility that a patient has LTBI. Accordingly, in immunosuppressed RA patients with risk factors for LTBI and negative initial screening tests, the panel recommends that a repeat TST or IGRA could be considered 1–3 weeks after the initial negative screening (see diamond A of Figure 3 in the original guideline document).

   If the RA patient has active or latent TB based on the test results, the panel recommends appropriate antitubercular treatment and consideration of referral to a specialist. Treatment with biologic agents can be initiated or resumed after 1 month of latent TB treatment with antitubercular medications and after completion of the treatment of active TB, as applicable (see Figure 3 in the original guideline document).

   The panel recommends annual testing in RA patients who live, travel, or work in situations where TB exposure is likely while they continue treatment with biologic agents (see diamond D of Figure 3 in the original guideline document). Patients who test positive for TST or IGRA at baseline can remain positive for these tests even after successful treatment of TB. These patients need monitoring for clinical signs and symptoms of recurrent TB, since repeating tests will not help in the diagnosis of recurrent TB.

4. Vaccination in Patients Starting or Currently Receiving DMARDs or Biologic Agents as Part of Their RA Therapy (level of evidence C for all recommendations)

   The panel recommends that all killed (pneumococcal, influenza intramuscular, and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer), and live attenuated (herpes zoster) vaccinations should be undertaken before starting a DMARD or a biologic agent (see Table 5 in the original guideline document).

   It also recommends that, if not previously done, vaccination with indicated pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed), and HPV vaccine (recombinant) should be undertaken in RA patients already taking a DMARD or a biologic agent (see Table 5 in the original guideline document).

   The panel recommends vaccination with herpes zoster vaccine in RA patients already taking a DMARD. All vaccines should be given based on age and risk, and physicians should refer to vaccine instructions and CDC recommendations for details about dosing and timing issues related to vaccinations.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials.
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies.
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care.

Note: Level C evidence often denoted a circumstance where medical literature addressed the general topic under discussion but it did not address the specific clinical situations or scenarios reviewed by the panel.

The levels of evidence supporting the recommendations (A-C) are defined at the end of the "Major Recommendations" field.

Recommendations for the Use of Disease-Modifying Antirheumatic Drugs (DMARDs) and Biologic Agents in Patients Who Qualify for Treatment of Rheumatoid Arthritis (RA)

This 2012 American College of Rheumatology (ACR) recommendations update incorporates the evidence from systematic literature review synthesis and recommendations from 2008 and rates updated and new clinical scenarios regarding the use of DMARDs and biologic agents for the treatment of RA. Terms used in the recommendations are defined in Table 2 of the original guideline document. The 2012 recommendations are listed in the 4 sections below and in the following order:

1. Indications for and switching DMARDs and biologic agents: early RA (indications, see Figure 1 in the original guideline document) followed by established RA (indications and switching, see Figure 2 in the original guideline document), along with details of the level of evidence supporting these recommendations (see Supplementary Appendix 7, available in the online version at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 
   
   )
2. Use of biologic agents in patients with hepatitis, malignancy, or congestive heart failure (CHF) who qualify for RA management (see Table 4 in the original guideline document)
3. Screening for tuberculosis (TB) in patients starting or currently receiving biologic agents as part of their RA therapy (see Figure 3 in the original guideline document)
4. Vaccination in patients starting or currently receiving DMARDs or biologic agents as part of their RA therapy (see Table 5 in the original guideline document)

The recommendations in the text below and in Tables 4 and 5 in the original guideline document represent the results of the 2012 update only, whereas Figures 1–3 in the original guideline document also incorporate some of the 2008 ACR RA recommendations that did not change. Areas of uncertainty by the panel (that did not lead to recommendations) are noted in Supplementary Appendix 8 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

1. Indications for Starting, Resuming, Adding, or Switching DMARDs or Biologic Agents

   The panel first describes a recommendation targeting remission or low disease activity in RA (section 1A). This is followed by recommendations for DMARD or biologic agent use in early RA (section 1B). Next, the panel provides recommendations for initiating and switching between DMARDs and biologic agents in established RA (section 1C).

   1A. Target Low Disease Activity or Remission

   The panel recommends targeting either low disease activity (see Table 3 in the original guideline document) or remission (see Table 2 in the original guideline document) in all patients with early RA (see Figure 1 in the original guideline document; level of evidence C) and established RA (see Figure 2 in the original guideline document; level of evidence C) receiving any DMARD or biologic agent.

   1B. Early RA (Disease Duration <6 Months)

   In patients with early RA, the panel recommends the use of DMARD monotherapy both for low disease activity and for moderate or high disease activity with the absence of poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C) (details are shown in Supplementary Appendix 7, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

   
   ).

   In patients with early RA, the panel recommends the use of DMARD combination therapy (including double and triple therapy) in patients with moderate or high disease activity plus poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C).

   In patients with early RA, the panel also recommends the use of an anti-tumor necrosis factor (anti-TNF) biologic with or without methotrexate in patients who have high disease activity with poor prognostic features (see Figure 1 in the original guideline document; level of evidence A and B). Infliximab is the only exception and the recommendation is to use it in combination with methotrexate, but not as monotherapy.

   1C. Established RA (Disease Duration ≥6 Months or Meeting the 1987 ACR RA Classification Criteria)

   The remainder of panel recommendations regarding indications for DMARDs and biologic agents are for patients with established RA. The 3 subsections below define recommendations for initiating and switching therapies in established RA (see Figure 2 in the original guideline document). Where the prognosis is not mentioned, the recommendation to use/switch to a DMARD or a biologic agent applies to all patients, regardless of prognostic features.

   Initiating and Switching Among DMARDs

   If after 3 months of DMARD monotherapy (in patients without poor prognostic features), a patient deteriorates from low to moderate/high disease activity, then methotrexate, hydroxychloroquine, or leflunomide should be added (see rectangle A of Figure 2 in the original guideline document; level of evidence A and B).

   If after 3 months of methotrexate or methotrexate/DMARD combination, a patient still has moderate or high disease activity, then add another non-methotrexate DMARD or switch to a different non-methotrexate DMARD (see rectangle B of Figure 2 in the original guideline document; level of evidence B and C).

   Switching from DMARDs to Biologic Agents

   If a patient has moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy, as an alternative to the DMARD recommendation just noted above, the panel recommends adding or switching to an anti-TNF biologic, abatacept, or rituximab (see rectangles C and D of Figure 2 in the original guideline document; level of evidence A–C).

   If after 3 months of intensified DMARD combination therapy or after a second DMARD, a patient still has moderate or high disease activity, add or switch to an anti-TNF biologic (see rectangle C of Figure 2 in the original guideline document; level of evidence C).

   Switching Among Biologic Agents Due to Lack of Benefit or Loss of Benefit

   If a patient still has moderate or high disease activity after 3 months of anti-TNF biologic therapy and this is due to a lack or loss of benefit, switching to another anti-TNF biologic or a non-TNF biologic is recommended (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient still has moderate or high disease activity after 6 months of a non-TNF biologic and the failure is due to a lack or loss of benefit, switch to another non-TNF biologic or an anti-TNF biologic (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C). An assessment period of 6 months was chosen rather than 3 months, due to the anticipation that a longer time may be required for efficacy of a non-TNF biologic.

   Switching Among Biologic Agents Due to Harms/Adverse Events

   If a patient has high disease activity after failing an anti-TNF biologic because of a serious adverse event, switch to a non-TNF biologic (see rectangle E of Figure 2 in the original guideline document; level of evidence C).

   If a patient has moderate or high disease activity after failing an anti-TNF biologic because of a nonserious adverse event, switch to another anti-TNF biologic or a non-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient has moderate or high disease activity after failing a non-TNF biologic because of an adverse event (serious or nonserious), switch to another non-TNF biologic or an anti-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence C).

2. Use of Biologic Agents in RA Patients With Hepatitis, Malignancy, or Chronic Heart Failure (CHF), Qualifying for More Aggressive Treatment (level of evidence C for all recommendations)

   Hepatitis B or C

   The panel recommends that etanercept could potentially be used in RA patients with hepatitis C requiring RA treatment (see Table 4 in the original guideline document).

   The panel also recommends not using biologic agents in RA patients with untreated chronic hepatitis B (disease not treated due to contraindications to treatment or intolerable adverse events) and in RA patients with treated chronic hepatitis B with Child-Pugh class B and higher (see Table 4 in the original guideline document; for details of Child-Pugh classification, see Table 2 in the original guideline document). The panel did not make recommendations regarding the use of any biologic agent for treatment in RA patients with a history of hepatitis B and a positive hepatitis B core antibody.

   Malignancies

   For patients who have been treated for solid malignancies more than 5 years ago or who have been treated for nonmelanoma skin cancer more than 5 years ago, the panel recommends starting or resuming any biologic agent if those patients would otherwise qualify for this RA management strategy (see Table 4 in the original guideline document).

   The panel only recommends starting or resuming rituximab in RA patients with: 1) a previously treated solid malignancy within the last 5 years, 2) a previously treated nonmelanoma skin cancer within the last 5 years, 3) a previously treated melanoma skin cancer, or 4) a previously treated lymphoproliferative malignancy. Little is known about the effects of biologic therapy in patients with a history of a solid cancer within the past 5 years owing to the exclusion of such patients from participation in clinical trials and the lack of studies examining the risk of recurrent cancer in this subgroup of patients.

   CHF

   The panel recommends not using an anti-TNF biologic in RA patients with CHF that is New York Heart Association (NYHA) class III or IV and who have an ejection fraction of 50% or less (see Table 4 in the original guideline document).

3. TB Screening for Biologic Agents (level of evidence C for all recommendations except for initiation of biologic agents in patients being treated for latent TB infection [LTBI], where the level of evidence is B)

   The panel recommends screening to identify LTBI in all RA patients being considered for therapy with biologic agents, regardless of the presence of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends that clinicians assess the patient's medical history to identify risk factors for TB (specified by the Centers for Disease Control and Prevention [CDC]) (see Table 2 in the original guideline document).

   The panel recommends the tuberculin skin test (TST) or interferon-gamma–release assays (IGRAs) as the initial test in all RA patients starting biologic agents, regardless of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends the use of the IGRA over the TST in patients who had previously received a bacillus Calmette-Guerin (BCG) vaccination, due to the high false-positive test rates for TST (see Figure 3 in the original guideline document).

   The panel recommends that RA patients with a positive initial or repeat TST or IGRA should have a chest radiograph and, if suggestive of active TB, a subsequent sputum examination to check for the presence of active TB (see diamonds B and C of Figure 3 in the original guideline document). RA patients with a negative screening TST or IGRA may not need further evaluation in the absence of risk factors and/or clinical suspicion for TB. Since patients with RA may have false-negative TST or IGRA results due to immunosuppression, a negative TST or IGRA should not be interpreted as excluding the possibility that a patient has LTBI. Accordingly, in immunosuppressed RA patients with risk factors for LTBI and negative initial screening tests, the panel recommends that a repeat TST or IGRA could be considered 1–3 weeks after the initial negative screening (see diamond A of Figure 3 in the original guideline document).

   If the RA patient has active or latent TB based on the test results, the panel recommends appropriate antitubercular treatment and consideration of referral to a specialist. Treatment with biologic agents can be initiated or resumed after 1 month of latent TB treatment with antitubercular medications and after completion of the treatment of active TB, as applicable (see Figure 3 in the original guideline document).

   The panel recommends annual testing in RA patients who live, travel, or work in situations where TB exposure is likely while they continue treatment with biologic agents (see diamond D of Figure 3 in the original guideline document). Patients who test positive for TST or IGRA at baseline can remain positive for these tests even after successful treatment of TB. These patients need monitoring for clinical signs and symptoms of recurrent TB, since repeating tests will not help in the diagnosis of recurrent TB.

4. Vaccination in Patients Starting or Currently Receiving DMARDs or Biologic Agents as Part of Their RA Therapy (level of evidence C for all recommendations)

   The panel recommends that all killed (pneumococcal, influenza intramuscular, and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer), and live attenuated (herpes zoster) vaccinations should be undertaken before starting a DMARD or a biologic agent (see Table 5 in the original guideline document).

   It also recommends that, if not previously done, vaccination with indicated pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed), and HPV vaccine (recombinant) should be undertaken in RA patients already taking a DMARD or a biologic agent (see Table 5 in the original guideline document).

   The panel recommends vaccination with herpes zoster vaccine in RA patients already taking a DMARD. All vaccines should be given based on age and risk, and physicians should refer to vaccine instructions and CDC recommendations for details about dosing and timing issues related to vaccinations.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials.
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies.
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care.

Note: Level C evidence often denoted a circumstance where medical literature addressed the general topic under discussion but it did not address the specific clinical situations or scenarios reviewed by the panel.

The levels of evidence supporting the recommendations (A-C) are defined at the end of the "Major Recommendations" field.

Recommendations for the Use of Disease-Modifying Antirheumatic Drugs (DMARDs) and Biologic Agents in Patients Who Qualify for Treatment of Rheumatoid Arthritis (RA)

This 2012 American College of Rheumatology (ACR) recommendations update incorporates the evidence from systematic literature review synthesis and recommendations from 2008 and rates updated and new clinical scenarios regarding the use of DMARDs and biologic agents for the treatment of RA. Terms used in the recommendations are defined in Table 2 of the original guideline document. The 2012 recommendations are listed in the 4 sections below and in the following order:

1. Indications for and switching DMARDs and biologic agents: early RA (indications, see Figure 1 in the original guideline document) followed by established RA (indications and switching, see Figure 2 in the original guideline document), along with details of the level of evidence supporting these recommendations (see Supplementary Appendix 7, available in the online version at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 
   
   )
2. Use of biologic agents in patients with hepatitis, malignancy, or congestive heart failure (CHF) who qualify for RA management (see Table 4 in the original guideline document)
3. Screening for tuberculosis (TB) in patients starting or currently receiving biologic agents as part of their RA therapy (see Figure 3 in the original guideline document)
4. Vaccination in patients starting or currently receiving DMARDs or biologic agents as part of their RA therapy (see Table 5 in the original guideline document)

The recommendations in the text below and in Tables 4 and 5 in the original guideline document represent the results of the 2012 update only, whereas Figures 1–3 in the original guideline document also incorporate some of the 2008 ACR RA recommendations that did not change. Areas of uncertainty by the panel (that did not lead to recommendations) are noted in Supplementary Appendix 8 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

1. Indications for Starting, Resuming, Adding, or Switching DMARDs or Biologic Agents

   The panel first describes a recommendation targeting remission or low disease activity in RA (section 1A). This is followed by recommendations for DMARD or biologic agent use in early RA (section 1B). Next, the panel provides recommendations for initiating and switching between DMARDs and biologic agents in established RA (section 1C).

   1A. Target Low Disease Activity or Remission

   The panel recommends targeting either low disease activity (see Table 3 in the original guideline document) or remission (see Table 2 in the original guideline document) in all patients with early RA (see Figure 1 in the original guideline document; level of evidence C) and established RA (see Figure 2 in the original guideline document; level of evidence C) receiving any DMARD or biologic agent.

   1B. Early RA (Disease Duration <6 Months)

   In patients with early RA, the panel recommends the use of DMARD monotherapy both for low disease activity and for moderate or high disease activity with the absence of poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C) (details are shown in Supplementary Appendix 7, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658 

   
   ).

   In patients with early RA, the panel recommends the use of DMARD combination therapy (including double and triple therapy) in patients with moderate or high disease activity plus poor prognostic features (see Figure 1 in the original guideline document; level of evidence A–C).

   In patients with early RA, the panel also recommends the use of an anti-tumor necrosis factor (anti-TNF) biologic with or without methotrexate in patients who have high disease activity with poor prognostic features (see Figure 1 in the original guideline document; level of evidence A and B). Infliximab is the only exception and the recommendation is to use it in combination with methotrexate, but not as monotherapy.

   1C. Established RA (Disease Duration ≥6 Months or Meeting the 1987 ACR RA Classification Criteria)

   The remainder of panel recommendations regarding indications for DMARDs and biologic agents are for patients with established RA. The 3 subsections below define recommendations for initiating and switching therapies in established RA (see Figure 2 in the original guideline document). Where the prognosis is not mentioned, the recommendation to use/switch to a DMARD or a biologic agent applies to all patients, regardless of prognostic features.

   Initiating and Switching Among DMARDs

   If after 3 months of DMARD monotherapy (in patients without poor prognostic features), a patient deteriorates from low to moderate/high disease activity, then methotrexate, hydroxychloroquine, or leflunomide should be added (see rectangle A of Figure 2 in the original guideline document; level of evidence A and B).

   If after 3 months of methotrexate or methotrexate/DMARD combination, a patient still has moderate or high disease activity, then add another non-methotrexate DMARD or switch to a different non-methotrexate DMARD (see rectangle B of Figure 2 in the original guideline document; level of evidence B and C).

   Switching from DMARDs to Biologic Agents

   If a patient has moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy, as an alternative to the DMARD recommendation just noted above, the panel recommends adding or switching to an anti-TNF biologic, abatacept, or rituximab (see rectangles C and D of Figure 2 in the original guideline document; level of evidence A–C).

   If after 3 months of intensified DMARD combination therapy or after a second DMARD, a patient still has moderate or high disease activity, add or switch to an anti-TNF biologic (see rectangle C of Figure 2 in the original guideline document; level of evidence C).

   Switching Among Biologic Agents Due to Lack of Benefit or Loss of Benefit

   If a patient still has moderate or high disease activity after 3 months of anti-TNF biologic therapy and this is due to a lack or loss of benefit, switching to another anti-TNF biologic or a non-TNF biologic is recommended (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient still has moderate or high disease activity after 6 months of a non-TNF biologic and the failure is due to a lack or loss of benefit, switch to another non-TNF biologic or an anti-TNF biologic (see rectangles F and G of Figure 2 in the original guideline document; level of evidence B and C). An assessment period of 6 months was chosen rather than 3 months, due to the anticipation that a longer time may be required for efficacy of a non-TNF biologic.

   Switching Among Biologic Agents Due to Harms/Adverse Events

   If a patient has high disease activity after failing an anti-TNF biologic because of a serious adverse event, switch to a non-TNF biologic (see rectangle E of Figure 2 in the original guideline document; level of evidence C).

   If a patient has moderate or high disease activity after failing an anti-TNF biologic because of a nonserious adverse event, switch to another anti-TNF biologic or a non-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence B and C).

   If a patient has moderate or high disease activity after failing a non-TNF biologic because of an adverse event (serious or nonserious), switch to another non-TNF biologic or an anti-TNF biologic (see rectangle F of Figure 2 in the original guideline document; level of evidence C).

2. Use of Biologic Agents in RA Patients With Hepatitis, Malignancy, or Chronic Heart Failure (CHF), Qualifying for More Aggressive Treatment (level of evidence C for all recommendations)

   Hepatitis B or C

   The panel recommends that etanercept could potentially be used in RA patients with hepatitis C requiring RA treatment (see Table 4 in the original guideline document).

   The panel also recommends not using biologic agents in RA patients with untreated chronic hepatitis B (disease not treated due to contraindications to treatment or intolerable adverse events) and in RA patients with treated chronic hepatitis B with Child-Pugh class B and higher (see Table 4 in the original guideline document; for details of Child-Pugh classification, see Table 2 in the original guideline document). The panel did not make recommendations regarding the use of any biologic agent for treatment in RA patients with a history of hepatitis B and a positive hepatitis B core antibody.

   Malignancies

   For patients who have been treated for solid malignancies more than 5 years ago or who have been treated for nonmelanoma skin cancer more than 5 years ago, the panel recommends starting or resuming any biologic agent if those patients would otherwise qualify for this RA management strategy (see Table 4 in the original guideline document).

   The panel only recommends starting or resuming rituximab in RA patients with: 1) a previously treated solid malignancy within the last 5 years, 2) a previously treated nonmelanoma skin cancer within the last 5 years, 3) a previously treated melanoma skin cancer, or 4) a previously treated lymphoproliferative malignancy. Little is known about the effects of biologic therapy in patients with a history of a solid cancer within the past 5 years owing to the exclusion of such patients from participation in clinical trials and the lack of studies examining the risk of recurrent cancer in this subgroup of patients.

   CHF

   The panel recommends not using an anti-TNF biologic in RA patients with CHF that is New York Heart Association (NYHA) class III or IV and who have an ejection fraction of 50% or less (see Table 4 in the original guideline document).

3. TB Screening for Biologic Agents (level of evidence C for all recommendations except for initiation of biologic agents in patients being treated for latent TB infection [LTBI], where the level of evidence is B)

   The panel recommends screening to identify LTBI in all RA patients being considered for therapy with biologic agents, regardless of the presence of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends that clinicians assess the patient's medical history to identify risk factors for TB (specified by the Centers for Disease Control and Prevention [CDC]) (see Table 2 in the original guideline document).

   The panel recommends the tuberculin skin test (TST) or interferon-gamma–release assays (IGRAs) as the initial test in all RA patients starting biologic agents, regardless of risk factors for LTBI (see diamond A of Figure 3 in the original guideline document). It recommends the use of the IGRA over the TST in patients who had previously received a bacillus Calmette-Guerin (BCG) vaccination, due to the high false-positive test rates for TST (see Figure 3 in the original guideline document).

   The panel recommends that RA patients with a positive initial or repeat TST or IGRA should have a chest radiograph and, if suggestive of active TB, a subsequent sputum examination to check for the presence of active TB (see diamonds B and C of Figure 3 in the original guideline document). RA patients with a negative screening TST or IGRA may not need further evaluation in the absence of risk factors and/or clinical suspicion for TB. Since patients with RA may have false-negative TST or IGRA results due to immunosuppression, a negative TST or IGRA should not be interpreted as excluding the possibility that a patient has LTBI. Accordingly, in immunosuppressed RA patients with risk factors for LTBI and negative initial screening tests, the panel recommends that a repeat TST or IGRA could be considered 1–3 weeks after the initial negative screening (see diamond A of Figure 3 in the original guideline document).

   If the RA patient has active or latent TB based on the test results, the panel recommends appropriate antitubercular treatment and consideration of referral to a specialist. Treatment with biologic agents can be initiated or resumed after 1 month of latent TB treatment with antitubercular medications and after completion of the treatment of active TB, as applicable (see Figure 3 in the original guideline document).

   The panel recommends annual testing in RA patients who live, travel, or work in situations where TB exposure is likely while they continue treatment with biologic agents (see diamond D of Figure 3 in the original guideline document). Patients who test positive for TST or IGRA at baseline can remain positive for these tests even after successful treatment of TB. These patients need monitoring for clinical signs and symptoms of recurrent TB, since repeating tests will not help in the diagnosis of recurrent TB.

4. Vaccination in Patients Starting or Currently Receiving DMARDs or Biologic Agents as Part of Their RA Therapy (level of evidence C for all recommendations)

   The panel recommends that all killed (pneumococcal, influenza intramuscular, and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer), and live attenuated (herpes zoster) vaccinations should be undertaken before starting a DMARD or a biologic agent (see Table 5 in the original guideline document).

   It also recommends that, if not previously done, vaccination with indicated pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed), and HPV vaccine (recombinant) should be undertaken in RA patients already taking a DMARD or a biologic agent (see Table 5 in the original guideline document).

   The panel recommends vaccination with herpes zoster vaccine in RA patients already taking a DMARD. All vaccines should be given based on age and risk, and physicians should refer to vaccine instructions and CDC recommendations for details about dosing and timing issues related to vaccinations.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials.
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies.
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care.

Note: Level C evidence often denoted a circumstance where medical literature addressed the general topic under discussion but it did not address the specific clinical situations or scenarios reviewed by the panel.

Renal Biopsy and Histology

The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.

Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus

RBCs = red blood cells; hpf = high-power field.

The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.

Adjunctive Treatments

The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.

All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.

The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m² (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.

Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).

Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis

The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.

The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.

Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.

There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m² IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.

Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.

Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.

The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).

Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.

Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents

The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.

Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN

The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).

Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.

Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy

The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.

Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy

In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.

There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.

Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.

If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.

The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.

Identification of Vascular Disease in Patients with SLE and Renal Abnormalities

Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)

Treatment of LN in Patients Who Are Pregnant

The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.

Monitoring Activity of LN

Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).

Table. Recommended Monitoring of Lupus Nephritis*

*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care

Renal Biopsy and Histology

The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.

Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus

RBCs = red blood cells; hpf = high-power field.

The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.

Adjunctive Treatments

The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.

All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.

The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m² (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.

Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).

Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis

The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.

The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.

Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.

There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m² IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.

Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.

Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.

The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).

Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.

Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents

The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.

Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN

The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).

Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.

Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy

The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.

Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy

In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.

There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.

Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.

If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.

The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.

Identification of Vascular Disease in Patients with SLE and Renal Abnormalities

Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)

Treatment of LN in Patients Who Are Pregnant

The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.

Monitoring Activity of LN

Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).

Table. Recommended Monitoring of Lupus Nephritis*

*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care

Renal Biopsy and Histology

The Task Force Panel recommended that all patients with clinical evidence of active lupus nephritis (LN), previously untreated, undergo renal biopsy (unless strongly contraindicated) so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (level C evidence) (see Table 1 in the original guideline document for ISN/RPS classification of LN). In addition, disease can be evaluated for activity and chronicity and for tubular and vascular changes. Finally, biopsies may identify additional or alternative causes of renal disease, such as tubular necrosis related to medications, hypovolemia, or hypotension. Biopsy is most highly recommended in patients with the characteristics indicated in the following table.

Table. Indications for Renal Biopsy in Patients with Systemic Lupus Erythematosus

RBCs = red blood cells; hpf = high-power field.

The Task Force Panel recommended that treatment be based in large part on the classification of type of LN by these ISN/RPS criteria. As a result, the following recommendations are presented according to the histologic classification of nephritis. The Task Force Panel agreed that class I (minimal mesangial immune deposits on immunofluorescence with normal light microscopy) and class II (mesangial hypercellularity or matrix expansion on light microscopy with immune deposits confined to mesangium on immunofluorescence) generally do not require immunosuppressive treatment (level C evidence). In general, patients with class III (subendothelial immune deposits and proliferative changes in <50% of glomeruli) and class IV (subendothelial deposits and proliferative glomerular changes involving ≥50% of glomeruli) require aggressive therapy with glucocorticoids and immunosuppressive agents. Class V (subepithelial immune deposits and membranous thickening of glomerular capillaries) when combined with class III or IV should be treated in the same manner as class III or IV. Class V alone ("pure membranous LN") may be approached somewhat differently, as indicated below under "Recommendations for Induction of Improvement in Patients with Class V 'Pure Membranous' LN". Histologic class VI (sclerosis of ≥90% of glomeruli) generally requires preparation for renal replacement therapy rather than immunosuppression. The designations "A" and "C" indicate whether active or chronic changes are present; the higher the chronicity the less likely that the nephritis will respond to immunosuppression. However, A or C classifications were not included in the entry criteria for clinical trials in LN published to date, and therefore they are not considered in the recommendations.

Adjunctive Treatments

The Task Force Panel recommended that all systemic lupus erythematosus (SLE) patients with nephritis be treated with a background of hydroxychloroquine (HCQ; level C evidence), unless there is a contraindication.

All LN patients with proteinuria ≥0.5 gm per 24 hours (or equivalent by protein/creatinine ratios on spot urine samples) should have blockade of the renin–angiotensin system, which drives intraglomerular pressure (level A evidence for nondiabetic chronic renal disease). Treatment with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria by approximately 30%, and significantly delays doubling of serum creatinine and progression to end-stage renal disease in patients with nondiabetic chronic renal disease. These classes of medications are contraindicated in pregnancy. The use of combination ACE inhibitors/ARB therapies is controversial. ACE inhibitors or ARB treatments are superior to calcium-channel blockers and diuretics alone in preserving renal function in chronic kidney disease.

The Task Force Panel recommended that careful attention be paid to control of hypertension, with a target of ≤130/80 mm Hg (level A evidence for nondiabetic chronic renal disease). The Task Force Panel also recommended that statin therapy be introduced in patients with low-density lipoprotein cholesterol >100 mg/dl (level C evidence). Note that a glomerular filtration rate <60 ml/minute/1.73 m² (equivalent to a serum creatinine level >1.5 mg/dl or 133 µmoles/liter) is a risk factor for accelerated atherosclerosis. SLE itself is also an independent risk factor for accelerated atherosclerosis.

Finally, the Task Force Panel recommended that women of child-bearing potential with active or prior LN receive counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence).

Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis

The Task Force Panel recommended mycophenolate mofetil (MMF) (2–3 gm total daily orally) or intravenous (IV) cyclophosphamide (CYC) along with glucocorticoids (level A evidence) (see Figure 2 in the original guideline document). MMF and CYC are considered equivalent based on recent high-quality studies, a meta-analysis, and expert opinion. Long-term studies with MMF are not as abundant as those with CYC; data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years. MMF has been similar in efficacy in all races studied to date (whites, Asians, African Americans, and Latin/Hispanic Americans). The Aspreva Lupus Management Study (ALMS) trial comparing response rates of LN to MMF plus glucocorticoids showed similar improvement in whites, Asians, and other races (primarily African Americans and Hispanics). However, The Task Force Panel voted that Asians compared to non-Asians might require lower doses of MMF for similar efficacy (level C evidence). Therefore, the physician might aim for 3 gm per day total daily highest dose in non-Asians and 2 gm per day in Asians. There is evidence that African Americans and Hispanics with LN respond less well to IV CYC than do patients of white or Asian races. MMF/mycophenolic acid (MPA) may be an initial choice more likely to induce improvement in patients who are African American or Hispanic.

The exact suggested dose of MMF varied based on the clinical scenario: for those with class III/IV without cellular crescents and for those with proteinuria and a stable creatinine for whom a renal biopsy sample cannot be obtained, both 2 gm and 3 gm total daily doses were acceptable to the Task Force Panel, while a dose of 3 gm daily was favored for those with class III/IV and crescents and for those with proteinuria and a recent significant rise in creatinine.

Some evidence suggests that MPA and enteric-coated mycophenolate sodium are less likely than MMF to cause nausea and diarrhea, but this is controversial, and the exact equivalency of the preparations is not firmly established. The Core Expert Panel recommended that MMF and MPA are likely to be equivalent in inducing improvement of LN, with 1,440–2,160 mg total daily dose of MPA roughly equivalent to 2,000–3,000 mg total daily dose of MMF. Some investigators have suggested that serum levels of MPA, the active metabolite of MMF, should be measured at the trough or peak (1 hour after a dose), and treatment of SLE should be guided by these levels. However, there are not enough data at this time to make recommendations for monitoring of drug levels.

There are two regimens of IV CYC recommended by the Task Force Panel: 1) low-dose "Euro-Lupus" CYC (500 mg IV once every 2 weeks for a total of 6 doses), followed by maintenance therapy with daily oral azathioprine (AZA) or daily oral MMF (level B evidence), and 2) high-dose CYC (500–1,000 mg/m² IV once a month for 6 doses), followed by maintenance treatment with MMF or AZA (level A evidence) (see Figure 2 in the original guideline document). If CYC is being considered for treatment, the Core Expert Panel recommended IV CYC at the low "Euro-Lupus" dose for white patients with Western European or Southern European racial/ethnic backgrounds (level B evidence). In European study patients, the low- and high-dose regimens were equivalent in efficacy, and serious infections were less frequent with the lower doses. The low- and high-dose regimens have not been compared in nonwhite racial groups. Ten years of followup comparing low- and high-dose regimens showed similar rates of LN flares, end-stage renal disease, and doubling of the serum creatinine.

Pulse IV glucocorticoids (500–1,000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended by the Task Force Panel, followed by daily oral glucocorticoids (0.5–1 mg/kg/day), followed by a taper to the minimal amount necessary to control disease (level C evidence). There are insufficient data to recommend a specific steroid taper because the nephritis and extrarenal manifestations vary from patient to patient. There was no consensus reached regarding the use of monthly IV methylprednisolone with monthly IV CYC.

Although AZA has been used to treat LN, the Task Force Panel did not recommend it as one of the first choices for induction therapy.

The panel recommends that most patients be followed for 6 months after initiation of induction treatment with either CYC or MMF before making major changes in treatment other than alteration of glucocorticoid doses, unless there is clear evidence of worsening at 3 months (50% or more worsening of proteinuria or serum creatinine; level A evidence).

Fertility issues are often a concern for young SLE patients with nephritis. In a discussion, the Task Force Panel recommended that MMF was preferable to CYC for patients who express a major concern with fertility preservation, since high-dose CYC can cause permanent infertility in both women and men (level A evidence of gonadal toxicity). Six months of high-dose IV CYC was associated with approximately 10% sustained infertility in young women, and higher rates in older women. If 6 months of CYC were followed by quarterly doses, there was a higher rate of infertility. The Task Force Panel did not reach a consensus on the use of leuprolide in patients with SLE receiving CYC as a means to preserve fertility. They also noted that MMF is teratogenic (class D in US Food and Drug Administration [FDA] ranking). Therefore, the physician should be sure that a patient is not pregnant before prescribing MMF or MPA, and the medications should be stopped for at least 6 weeks before pregnancy is attempted.

Recommendations for Induction of Improvement in Patients with Class IV or IV/V Plus Cellular Crescents

The Task Force Panel recommended either CYC or MMF for induction of improvement in this type of LN (level C evidence), along with IV pulses of high-dose glucocorticoid and initiation of oral glucocorticoids at the higher-range dosage, 1 mg/kg/day orally (see Figure 2 in the original guideline document). For the purpose of these recommendations statements, the presence of any crescents on a renal biopsy sample was considered crescentic LN. Until recently, experts have favored high-dose IV CYC for treatment of LN with cellular crescents. In general, the presence of crescents indicates a poorer prognosis, even with appropriate treatment. Further recommendations for a pregnant patient with crescentic glomerulonephritis are provided in the section on "Treatment of LN in Patients Who Are Pregnant," below.

Recommendations for Induction of Improvement in Patients with Class V "Pure Membranous" LN

The Task Force Panel recommends that patients with pure class V LN and with nephrotic range proteinuria be started on prednisone (0.5 mg/kg/day) plus MMF 2–3 gm total daily dose (level A evidence) (see Figure 3 in the original guideline document).

Other therapies for membranous LN have been reported; however, the Task Force Panel did not reach consensus on a recommendation regarding those therapies.

Recommendations for Maintaining Improvement in Patients Who Respond to Induction Therapy

The Task Force Panel recommended that either AZA or MMF be used for maintenance therapy (level A evidence) (see Figure 2 in the original guideline document). The Task Force Panel did not vote on the rate of medication taper during the maintenance phase; to date, there are no adequate data to inform the physician regarding how rapidly AZA or MMF can be tapered or withdrawn.

Recommendations for Changing Therapies in Patients Who Do Not Respond Adequately to Induction Therapy

In patients who fail to respond after 6 months of treatment (based on the treating physician's clinical impression) with glucocorticoids plus MMF or CYC, the Task Force Panel recommends a switch of the immunosuppressive agent from either CYC to MMF, or from MMF to CYC, with these changes accompanied by IV pulses of glucocorticoids for 3 days (level C evidence) (see Figure 2 in the original guideline document). For CYC, either low dose or high dose can be used in white individuals, as discussed above in the section on "Recommendations for Induction of Improvement in Patients with ISN Class III/IV Lupus Glomerulonephritis," above. Evidence to support these opinions is not as strong as evidence for the efficacy of initial induction therapy. The panel also voted that in some cases rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of one induction therapy, or after the patient has failed both CYC and MMF treatments (level C evidence). The Task Force Panel did not reach consensus regarding the use of calcineurin inhibitors in this setting; however, there is evidence for their efficacy as an induction agent and in refractory disease.

There is evidence in open-label trials that LN may respond to rituximab treatment. Prospective, randomized, placebo-controlled trials did not show a significant difference between rituximab and placebo (on a background of MMF and glucocorticoids) after 1 year of treatment.

Evidence to support the use of cyclosporine or tacrolimus in LN is from open trials and recent prospective clinical trials; additional prospective trials are in progress. In a recent prospective trial, tacrolimus was equivalent to high-dose IV CYC in inducing complete and partial remissions of LN over a 6-month period. In another 4-year–long prospective trial, cyclosporine was similar to AZA in preventing renal flares in patients receiving maintenance therapy.

If nephritis is worsening in patients treated for 3 months with glucocorticoids plus CYC or MMF, the Task Force Panel recommended that the clinician can choose any of the alternative treatments discussed (level C evidence). Although combinations of MMF and calcineurin inhibitors and of rituximab and MMF are being studied and might be considered for those who have failed the recommended induction therapies, data are not robust enough at this time to include them for voting scenarios.

The FDA has approved belimumab for use in seropositive patients with SLE who have active disease in spite of prior therapies.

Identification of Vascular Disease in Patients with SLE and Renal Abnormalities

Several types of vascular involvement can occur in renal tissue of SLE, including vasculitis, fibrinoid necrosis with narrowing of small arteries/arterioles ("bland" vasculopathy), thrombotic microangiopathy, and renal vein thrombosis. In general, vasculitis is treated similarly to the more common forms of LN discussed above. Bland vasculopathy is highly associated with hypertension; it is not clear which comes first, SLE or hypertension. Thrombotic microangiopathy can be associated with a thrombotic thrombocytopenia–like picture. The Task Force Panel recommended that thrombotic microangiopathy be treated primarily with plasma exchange therapy (level C evidence)

Treatment of LN in Patients Who Are Pregnant

The Task Force Panel recommended several approaches for management of LN in women who are pregnant (all level C evidence) (see Figure 4 in the original guideline document). In patients with prior LN but no current evidence of systemic or renal disease activity, no nephritis medications are necessary. Patients with mild systemic activity may be treated with HCQ; this probably reduces activity of SLE during pregnancy. If clinically active nephritis is present, or there is substantial extrarenal disease activity, the clinician may prescribe glucocorticoids at doses necessary to control disease activity, and if necessary AZA can be added. High-dose glucocorticoid therapy in patients with SLE is associated with a high risk of maternal complications such as hypertension and diabetes mellitus. MMF, CYC, and methotrexate should be avoided because they are teratogenic in humans. Although AZA is listed as pregnancy category D in Micromedex, cross-sectional studies have shown that the risk of fetal abnormalities is low. The dose of AZA should not exceed 2 mg/kg in a pregnant woman. For patients with a persistently active nephritis with documented or suspected class III or IV with crescents, consideration of delivery after 28 weeks for a viable fetus is recommended.

Monitoring Activity of LN

Recommendations for monitoring LN are shown in the following table, and result from votes of the Task Force Panel (level C evidence).

Table. Recommended Monitoring of Lupus Nephritis*

*Values are the monthly intervals suggested as the minimum frequency at which the indicated laboratory tests should be measured in the systemic lupus erythematosus scenarios shown in the left-hand column. GN = glomerulonephritis.
†Opinion of authors based on a study published after the Task Force Panel had voted.

Definitions:

Level of Evidence

• Level of Evidence A: Data derived from multiple randomized clinical trials
• Level of Evidence B: Data derived from a single randomized trial, or nonrandomized studies
• Level of Evidence C: Only consensus opinion of experts, case studies, or standard-of-care

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

In Children with Epilepsy, Is Using Adjunctive Vagus Nerve Stimulation (VNS) Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 14 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction (responder rate). In the pooled analysis of 481 children, the responder rate was 55% (95% confidence interval [CI] 51%–59%), but there was significant heterogeneity in the data. Two of the 16 studies were not included in the analysis because either they did not provide information about responder rate or they included a significant number (>20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%–10%).

Recommendation

VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C).

Clinical Context

VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery.

In Patients with Lennox-Gastaut Syndrome (LGS), Is Using Adjunctive VNS Therapy for Seizure Frequency Reduction Better Than Not Using Adjunctive VNS Therapy for Seizure Frequency Reduction?

Conclusion

Based on data from 4 Class III studies, VNS is possibly effective in achieving >50% seizure frequency reduction in patients with LGS. The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out) yielded a 55% (95% CI 46%–64%) responder rate.

Recommendation

VNS may be considered in patients with LGS (Level C).

Clinical Context

The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy.

In Patients with Epilepsy, Is Using VNS Associated with Mood Improvement?

Conclusion

Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy.

Recommendation

In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C).

Clinical Context

Depression is a common comorbidity for people with epilepsy. VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. The evidence does not clearly support an independent effect on mood in this complex population.

In Patients with Epilepsy, Is VNS Use Associated with Reduced Seizure Frequency Over Time?

Conclusion

Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation.

Recommendation

VNS may be considered progressively effective in patients over multiple years of exposure (Level C).

Clinical Context

The loss of medication efficacy over time is a challenging aspect of epilepsy management. The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option.

In Patients Undergoing VNS Therapy, Does Rapid Stimulation (Usual VNS Settings Are 7 Seconds "On" and 30 Seconds "Off") Improve Seizure Frequency More Often Than Standard Stimulation Settings (30 Seconds "On" and 300 Seconds "Off")?

Conclusion

These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds "on," 30 seconds "off") used either after standard stimulation (30 seconds "on," 300 seconds "off") was unsuccessful or as an initial treatment setting.

Recommendation

Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence (Level U).

Clinical Context

Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed.

In Patients Undergoing VNS Therapy, Does Using Additional Magnet-Activated Stimulation Trains for Auras or at Seizure Onset Interrupt Seizures Relative to Not Using Additional Magnet-Induced Stimulation Trains for Auras or at Seizure Onset?

Conclusion

Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable).

Recommendation

Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C).

In Patients Undergoing VNS Therapy, Have New Safety Concerns Emerged Since the Last Assessment?

Clinical Context

Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. Video electroencephalogram (EEG) and electrocardiogram (ECG) monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy; in a cohort of 1,819 individuals followed 3,176.3 person-years from VNS implantation, the SUDEP rate was 5.5 per 1,000 over the first 2 years but only 1.7 per 1,000 thereafter. The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested.

In Children Undergoing VNS Therapy, Do Adverse Events (AEs) Differ from Those in Adults?

Clinical Context

Children may have greater risk for wound infection than adults due to behaviors more common in children. Extra vigilance in monitoring for occurrence of site infection in children should be undertaken.

Definitions:

Classification of Evidence for Therapeutic Intervention

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Screening and Diagnosis

What Clinical Evaluation Procedures and Screening and Diagnostic Tools Can Be Used to Accurately Identify Symptoms and Make Diagnoses of Emotional Disorders in Individuals with Multiple Sclerosis (MS)?

Conclusions and Recommendations

In individuals with MS, the Center for Neurologic Study Emotional Lability Scale (CNS-LS) is possibly effective and may be considered for screening for pseudobulbar affect (PBA) (Level C, 1 Class II study [Smith et al., 2004]). The General Health Questionnaire (GHQ) (Goldberg & Hillier, 1979) is possibly effective and may be considered for identifying individuals with broadly defined emotional disturbances (Level C, 1 Class II study [Rabins & Brooks, 1981]). The Beck Depression Inventory (BDI) (Beck et al., 1961) and a 2-question screen (Whooley et al., 1997) are possibly effective and may be considered for identifying individuals with major depressive disorder (MDD) (Level C, 1 Class II study each [Sullivan et al., 1995; Mohr et al., 2007]). There is insufficient evidence to support/refute using the Center for Epidemiologic Studies Depression Rating Scale (CES-D) (Radloff, 1977) to screen for depressive symptoms (Pandya, Metz, & Patten, 2005) or a single question to screen for MDD (Vahter et al., 2007) (Level U, 1 Class III study each); the possibility that somatic or neurovegetative symptoms negatively affect the accuracy of BDI results (Level U, 2 conflicting Class III studies) (Mohr et al., 1997; Randolph et al., 2000); and the use of specific instruments or clinical evaluation procedures to diagnose emotional disorders in individuals with MS (Level U).

Clinical Context

Because emotional disorders may be unrecognized in medical settings, validated screening tools might improve identification of individuals who could benefit from further evaluation and treatment. The true positive rate of a screening tool depends not only on its sensitivity but also on the point prevalence of the disorder in the population under study. Clinically, false-positive results are not a major concern because individuals with the conditions typically identified (e.g., adjustment and subthreshold depressive disorders) can benefit from further assessment. Administratively, however, screening tools with high false-positive rates unnecessarily increase resource use.

Treatments

What Are the Effective Treatments for Disorders of Mood in Individuals with MS?

Conclusion and Recommendations

For individuals with MS, a 16-week program of individual telephone-administered cognitive behavioral therapy (T-CBT) program is possibly effective and may be considered in treating depressive symptoms (Level C, 1 Class II study [Mohr et al., 2005], 1 Class III study [Mohr, et al., 2000]). There is insufficient evidence to support/refute the efficacy and use of 1) sertraline (Mohr et al., 2001), desipramine (Schiffer & Wineman, 1990), paroxetine (Ehde et al., 2008), individual in-person cognitive behavioral therapy (CBT) (Mohr et al., 2001), individual in-person CBT plus relaxation training (Foley et al., 1987), or CBT-based group therapy (Forman & Lincoln, 2010) for depressive symptoms; or 2) individual in-person CBT plus relaxation training (Foley et al., 1987), group relaxation and imagery (Maguire, 1996), or CBT-based group therapy (Forman & Lincoln, 2010) for anxiety (Level U, 1 Class III study each).

Clinical Context

There is evidence supporting the efficacy of pharmacologic and nonpharmacologic therapies for depressed mood and anxiety in individuals without MS. Despite the lack of evidence in individuals with MS, these therapies are frequently used to treat emotional disorders in this population.

What Are the Effective Treatments for Disorders of Affect in Individuals with MS?

Conclusion and Recommendations

Dextromethorphan and quinidine (DM/Q) is possibly effective and safe and may be considered for treating individuals with MS with PBA (Level C, 1 Class II study) (Panitch et al., 2006).

Clinical Context

DM/Q is the only drug approved by the US Food and Drug Administration for PBA treatment, although other drugs are used in clinical practice (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants). There are no randomized placebo-controlled trials of these other agents.

Definitions:

Classification of Evidence

Screening Articles

Class I: A statistical, population based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class II: A statistical, non-referral clinic based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.

Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion or a case report.

Diagnostic Articles

Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient's clinical status. Study results allow calculation of measures of diagnostic accuracy.

Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy.

Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy.

Class IV: Studies not meeting Class I, II, or III criteria including consensus, expert opinion, or a case report.

Therapeutic Articles

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

1. In patients with a first generalized convulsive seizure who have returned to their baseline clinical status, should antiepileptic therapy be initiated in the emergency department (ED) to prevent additional seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations.

   1. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first provoked seizure. Precipitating medical conditions should be identified and treated.
   2. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first unprovoked seizure without evidence of brain disease or injury.
   3. Emergency physicians may initiate antiepileptic medication* in the ED, or defer in coordination with other providers, for patients who experienced a first unprovoked seizure with a remote history of brain disease or injury.

   *Antiepileptic medication in this document refers to medications prescribed for seizure prevention.

2. In patients with a first unprovoked seizure who have returned to their baseline clinical status in the ED, should the patient be admitted to the hospital to prevent adverse events?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. Emergency physicians need not admit patients with a first unprovoked seizure who have returned to their clinical baseline in the ED.

3. In patients with a known seizure disorder in which resuming their antiepileptic medication in the ED is deemed appropriate, does the route of administration impact recurrence of seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. When resuming antiepileptic medication in the ED is deemed appropriate, the emergency physician may administer intravenous (IV) or oral medication at their discretion.

4. In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzodiazepine, which agent or agents should be administered next to terminate seizures?

   Patient Management Recommendations

   Level A recommendations. Emergency physicians should administer an additional antiepileptic medication in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level B recommendations. Emergency physicians may administer IV phenytoin, fosphenytoin, or valproate in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level C recommendations. Emergency physicians may administer IV levetiracetam, propofol, or barbiturates in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Definitions:

   Strength of Evidence

   Literature Classification Schema*

   Design/Class	Therapy†	Diagnosis‡	Prognosis§
   1	Randomized, controlled trial or meta-analysis of randomized trials	Prospective cohort using a criterion standard or meta-analysis of prospective studies	Population prospective cohort or meta-analysis of prospective studies
   2	Nonrandomized trial	Retrospective observational	Retrospective cohort Case control
   3	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)

   *Some designs (e.g., surveys) will not fit this schema and should be assessed individually.

   †Objective is to measure therapeutic efficacy comparing interventions.

   ‡Objective is to determine the sensitivity and specificity of diagnostic tests.

   §Objective is to predict outcome including mortality and morbidity.

   Approach to Downgrading Strength of Evidence*

   	Design/Class
   Downgrading	1	2	3
   None	I	II	III
   1 level	II	III	X
   2 levels	III	X	X
   Fatally flawed	X	X	X

   *See the "Description of Methods Used to Analyze the Evidence" field for more information.

   Strength of recommendations regarding each critical question were made by subcommittee members using results from strength of evidence grading, expert opinion, and consensus among subcommittee members according to the following guidelines:

   Strength of Recommendations

   Level A recommendations. Generally accepted principles for patient care that reflect a high degree of clinical certainty (i.e., based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies).

   Level B recommendations. Recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (i.e., based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).

   Level C recommendations. Recommendations for patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus. In instances where consensus recommendations are made, "consensus" is placed in parentheses at the end of the recommendation.

   There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might lead to such a downgrading of recommendations.

1. In patients with a first generalized convulsive seizure who have returned to their baseline clinical status, should antiepileptic therapy be initiated in the emergency department (ED) to prevent additional seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations.

   1. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first provoked seizure. Precipitating medical conditions should be identified and treated.
   2. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first unprovoked seizure without evidence of brain disease or injury.
   3. Emergency physicians may initiate antiepileptic medication* in the ED, or defer in coordination with other providers, for patients who experienced a first unprovoked seizure with a remote history of brain disease or injury.

   *Antiepileptic medication in this document refers to medications prescribed for seizure prevention.

2. In patients with a first unprovoked seizure who have returned to their baseline clinical status in the ED, should the patient be admitted to the hospital to prevent adverse events?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. Emergency physicians need not admit patients with a first unprovoked seizure who have returned to their clinical baseline in the ED.

3. In patients with a known seizure disorder in which resuming their antiepileptic medication in the ED is deemed appropriate, does the route of administration impact recurrence of seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. When resuming antiepileptic medication in the ED is deemed appropriate, the emergency physician may administer intravenous (IV) or oral medication at their discretion.

4. In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzodiazepine, which agent or agents should be administered next to terminate seizures?

   Patient Management Recommendations

   Level A recommendations. Emergency physicians should administer an additional antiepileptic medication in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level B recommendations. Emergency physicians may administer IV phenytoin, fosphenytoin, or valproate in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level C recommendations. Emergency physicians may administer IV levetiracetam, propofol, or barbiturates in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Definitions:

   Strength of Evidence

   Literature Classification Schema*

   Design/Class	Therapy†	Diagnosis‡	Prognosis§
   1	Randomized, controlled trial or meta-analysis of randomized trials	Prospective cohort using a criterion standard or meta-analysis of prospective studies	Population prospective cohort or meta-analysis of prospective studies
   2	Nonrandomized trial	Retrospective observational	Retrospective cohort Case control
   3	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)

   *Some designs (e.g., surveys) will not fit this schema and should be assessed individually.

   †Objective is to measure therapeutic efficacy comparing interventions.

   ‡Objective is to determine the sensitivity and specificity of diagnostic tests.

   §Objective is to predict outcome including mortality and morbidity.

   Approach to Downgrading Strength of Evidence*

   	Design/Class
   Downgrading	1	2	3
   None	I	II	III
   1 level	II	III	X
   2 levels	III	X	X
   Fatally flawed	X	X	X

   *See the "Description of Methods Used to Analyze the Evidence" field for more information.

   Strength of recommendations regarding each critical question were made by subcommittee members using results from strength of evidence grading, expert opinion, and consensus among subcommittee members according to the following guidelines:

   Strength of Recommendations

   Level A recommendations. Generally accepted principles for patient care that reflect a high degree of clinical certainty (i.e., based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies).

   Level B recommendations. Recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (i.e., based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).

   Level C recommendations. Recommendations for patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus. In instances where consensus recommendations are made, "consensus" is placed in parentheses at the end of the recommendation.

   There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might lead to such a downgrading of recommendations.

1. In patients with a first generalized convulsive seizure who have returned to their baseline clinical status, should antiepileptic therapy be initiated in the emergency department (ED) to prevent additional seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations.

   1. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first provoked seizure. Precipitating medical conditions should be identified and treated.
   2. Emergency physicians need not initiate antiepileptic medication* in the ED for patients who have had a first unprovoked seizure without evidence of brain disease or injury.
   3. Emergency physicians may initiate antiepileptic medication* in the ED, or defer in coordination with other providers, for patients who experienced a first unprovoked seizure with a remote history of brain disease or injury.

   *Antiepileptic medication in this document refers to medications prescribed for seizure prevention.

2. In patients with a first unprovoked seizure who have returned to their baseline clinical status in the ED, should the patient be admitted to the hospital to prevent adverse events?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. Emergency physicians need not admit patients with a first unprovoked seizure who have returned to their clinical baseline in the ED.

3. In patients with a known seizure disorder in which resuming their antiepileptic medication in the ED is deemed appropriate, does the route of administration impact recurrence of seizures?

   Patient Management Recommendations

   Level A recommendations. None specified.

   Level B recommendations. None specified.

   Level C recommendations. When resuming antiepileptic medication in the ED is deemed appropriate, the emergency physician may administer intravenous (IV) or oral medication at their discretion.

4. In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzodiazepine, which agent or agents should be administered next to terminate seizures?

   Patient Management Recommendations

   Level A recommendations. Emergency physicians should administer an additional antiepileptic medication in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level B recommendations. Emergency physicians may administer IV phenytoin, fosphenytoin, or valproate in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Level C recommendations. Emergency physicians may administer IV levetiracetam, propofol, or barbiturates in ED patients with refractory status epilepticus who have failed treatment with benzodiazepines.

   Definitions:

   Strength of Evidence

   Literature Classification Schema*

   Design/Class	Therapy†	Diagnosis‡	Prognosis§
   1	Randomized, controlled trial or meta-analysis of randomized trials	Prospective cohort using a criterion standard or meta-analysis of prospective studies	Population prospective cohort or meta-analysis of prospective studies
   2	Nonrandomized trial	Retrospective observational	Retrospective cohort Case control
   3	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)	Case series Case report Other (e.g., consensus, review)

   *Some designs (e.g., surveys) will not fit this schema and should be assessed individually.

   †Objective is to measure therapeutic efficacy comparing interventions.

   ‡Objective is to determine the sensitivity and specificity of diagnostic tests.

   §Objective is to predict outcome including mortality and morbidity.

   Approach to Downgrading Strength of Evidence*

   	Design/Class
   Downgrading	1	2	3
   None	I	II	III
   1 level	II	III	X
   2 levels	III	X	X
   Fatally flawed	X	X	X

   *See the "Description of Methods Used to Analyze the Evidence" field for more information.

   Strength of recommendations regarding each critical question were made by subcommittee members using results from strength of evidence grading, expert opinion, and consensus among subcommittee members according to the following guidelines:

   Strength of Recommendations

   Level A recommendations. Generally accepted principles for patient care that reflect a high degree of clinical certainty (i.e., based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies).

   Level B recommendations. Recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (i.e., based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).

   Level C recommendations. Recommendations for patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus. In instances where consensus recommendations are made, "consensus" is placed in parentheses at the end of the recommendation.

   There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might lead to such a downgrading of recommendations.