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Title:
Initiation and Safety Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features

Author(s):
Mehrnoush Hassas Yeganeh MD*, Shokouh Hashemi, Neda Zafari, Mahsa sardari

Affiliattion(s):
Shahid Beheshti University of Medical Sciences, Tehran, Iran

* Corresponding Author

Vol 2, Num 1, January 2015

 

   

General Medication Usage

The ACR considered the general usage of intraarticular glucocorticoid injections and the use of methotrexate when initiating TNFα inhibitors.

Glucocorticoid joint injections—The use of glucocorticoid joint injections for active arthritis was recommended, regardless of concurrent therapy (no DMARD, nonbiologic DMARD, or biologic DMARD) or JIA treatment group (level C).(1-18) Triamcinolone hexacetonide, owing to its demonstrated superior efficacy should be the preferred Glucocorticoid for intraarticular injection. (level A).(5,6) Intraarticular glucocorticoid injections are expected to result in clinical improvement of arthritis for at least 4 months (level A).(2, 19) A shorter duration of clinical response may imply a need for escalation of systemic therapy. Intraarticular glucocorticoid injections that result in clinical improvement of arthritis for at least 4 months may be repeated as needed (level B).(3, 6, 10,17,18)

Methotrexate with TNFα inhibitors—The patients who had a partial previous clinical response to methotrexate are recommended to receive methotrexate when initiating a TNFα inhibitor (etanercept or adalimumab) (level B).(20) The ACR did not reach agreement on continuing or discontinuing methotrexate when initiating a TNFα inhibitor (etanercept or adalimumab) for patients who had a poor previous clinical response to methotrexate. The appropriateness of continuing methotrexate when initiating infliximab was assumed and was not evaluated by the ACR, owing to the recognized potential for methotrexate to reduce the incidence of neutralizing antibodies to infliximab (21) and consistent with the labeling of infliximab.(22)

Initiation of Therapeutic Agents

History of arthritis of 4 or fewer joints

The definitions of disease activity and features of poor prognosis for this treatment group are listed in Table 1. A diagram of the overall treatment strategy is shown in Figure 1.

NSAID monotherapy—Initiation of NSAID monotherapy (without glucocorticoid joint injection) was recommended as one treatment approach for patients with low disease activity, without joint contracture, and without features of poor prognosis (level B).(23-29) Continuation of NSAID monotherapy (without additional therapy) for longer than 2 months was inappropriate for patients with active arthritis.

Intraarticular glucocorticoid injections—Intraarticular glucocorticoid injections (with or without additional therapy) were recommended for all patients with active arthritis, irrespective of disease activity level, prognostic features, or joint contracture (level C).(1-19) As stated above, glucocorticoid joint injections should be performed with triamcinolone hexacetonide (level A) (5) and are expected to result in clinical improvement of arthritis for at least 4 months (level A).(2-19) A shorter duration of clinical improvement may imply a need for escalation of systemic therapy. Glucocorticoid injections that result in clinical improvement of arthritis for at least 4 months can be repeated as needed (level B).(3, 6, 10, 17, 18)

Methotrexate—Initiation of methotrexate was recommended as initial treatment (without prior therapy) for patients with high disease activity and features of poor prognosis (level C).(30-37) Following initial glucocorticoid joint injection(s), initiation of methotrexate was recommended for patients with high disease activity without features of poor prognosis and for patients with moderate disease activity and features of poor prognosis (level C).(30-37) Following repeated glucocorticoid injections, initiation of methotrexate was recommended for patients with moderate disease activity without features of poor prognosis and for patients with low disease activity and features of poor prognosis (level C).(30-37)

Sulfasalazine—Initiation of sulfasalazine was recommended following glucocorticoid joint injection or an adequate trial of NSAIDs for patients with the enthesitis-related arthritis category of JIA with moderate or high disease activity, irrespective of features of poor prognosis (level B).(38) Initiation of sulfasalazine was uncertain for patients who are not diagnosed with the enthesitis-related arthritis category of JIA.

TNFα inhibitors—Initiation of a TNFα inhibitor was recommended for patients who have received glucocorticoid joint injections and 3 months of methotrexate at the maximum tolerated typical dose and have moderate or high disease activity and features of poor prognosis (level C).(39, 40) Initiation of a TNFα inhibitor was also recommended for patients who have received glucocorticoid joint injections and 6 months of methotrexate and have high disease activity without features of poor prognosis (level C).(39, 40) Additionally, initiation of a TNFα inhibitor was recommended for patients specifically with the enthesitis-related arthritis category of JIA who have received glucocorticoid joint injections and an adequate trial of sulfasalazine (without prior methotrexate) and have moderate or high disease activity, irrespective of prognostic features (level C).(41,42)

Abatacept—Initiation of abatacept was uncertain prior to initiation of a TNFα inhibitor.

Hydroxychloroquine—Initiation of hydroxychloroquine monotherapy (with or without concurrent NSAIDs) was inappropriate for patients with active arthritis (level C).(43)

Leflunomide—Initiation of leflunomide was uncertain.

Nonbiologic DMARD combinations—Initiation of nonbiologic DMARD combinations (methotrexate plus sulfasalazine and/or hydroxychloroquine) was uncertain.

History of arthritis of 5 or more joints

The definitions of disease activity and features of poor prognosis for this treatment group are listed in Table 2. A diagram of the overall treatment strategy is shown in Figure 2.

NSAID monotherapy—Initiation of NSAID therapy alone (monotherapy without glucocorticoid joint injection) was uncertain for patients with active arthritis. Continuation of NSAID monotherapy for longer than 2 months was inappropriate for patients with active arthritis, irrespective of poor prognostic features (level C).(34, 44)

Methotrexate—Initiation of methotrexate was recommended as initial treatment for patients with high disease activity, irrespective of poor prognostic factors, and for patients with moderate disease activity and features of poor prognosis (level B).(30-34) Following approximately 1 month of NSAIDs, initiation of methotrexate was recommended for patients with low disease activity and features of poor prognosis (level B).(30-34) Following approximately 1 to 2 months of NSAIDs, initiation of methotrexate was recommended for patients with moderate disease activity without features of poor prognosis (level B).(30-34)

Leflunomide—The use of methotrexate is preferable over leflunomide, owing to greater personal and collective experience with methotrexate. However, initiation of leflunomide was recommended as one treatment approach as initial treatment for patients with high disease activity and features of poor prognosis (level B).(31) Following a brief trial of NSAIDs, initiation of leflunomide was recommended as one treatment approach for patients with high disease activity without features of poor prognosis and for patients with moderate disease activity with features of poor prognosis (level B).(31)

TNFα inhibitors—Initiation of a TNFα inhibitor was recommended for patients who have received methotrexate or leflunomide for 3 months at the maximum tolerated typical dose and have moderate or high disease activity, irrespective of poor prognostic features (level B).(39,40) Initiation of a TNFα inhibitor was also recommended for patients who have received methotrexate or leflunomide for 6 months and have low disease activity, irrespective of poor prognostic features (level B).(39,40) Switching from one TNFα inhibitor to another was recommended as one treatment approach for patients who have received the current TNFα inhibitor for 4 months and have moderate or high disease activity, irrespective of poor prognostic features (level C).(45, 46) Switching to a TNFα inhibitor was recommended as one treatment approach for patients who have received abatacept for 3 months and have high disease activity and features of poor prognosis and for patients who have received abatacept for 6 months and have moderate or high disease activity, irrespective of prognostic features (level D).

Abatacept—Initiation of abatacept was recommended as one treatment approach for patients who have received a TNFα inhibitor for 4 months and have high disease activity, irrespective of features of poor prognosis, or moderate disease activity and features of poor prognosis (level B).(47) Initiation of abatacept was recommended as one treatment approach for patients who have received more than one TNFα inhibitor sequentially and have moderate or high disease activity, irrespective of poor prognostic features, or low disease activity with features of poor prognosis (level B).(47)

Rituximab—Initiation of rituximab was recommended as one treatment approach for patients who have received a TNFα inhibitor and abatacept sequentially and have high disease activity, irrespective of poor prognostic features, or have moderate disease activity and features of poor prognosis (level C).(48-50) Although not formally assessed using the RAND/UCLA Appropriateness Method, rituximab may be more appropriate for patients who test positive for RF compared to patients who do not.

Anakinra—Initiation of anakinra was uncertain.

Hydroxychloroquine—Initiation of hydroxychloroquine monotherapy (with or without concurrent NSAIDs) was inappropriate for patients with active arthritis (level A).(43)

Sulfasalazine—Initiation of sulfasalazine was uncertain. Patients with the enthesitis-related arthritis category of JIA and history of arthritis of 5 or more joints were not independently considered by the TFP.

Nonbiologic DMARD combinations—Initiation of nonbiologic DMARD combinations (methotrexate plus sulfasalazine and/or hydroxychloroquine) was uncertain.

Active sacroiliac arthritis

Active sacroiliac arthritis was defined by the presence of clinical and imaging evidence. The definitions of disease activity and features of poor prognosis for this treatment group are listed in Table 3. The only medication class evaluated for this treatment group was the TNFα inhibitors.

TNFα inhibitors—In general, initiation of a TNFα inhibitor was recommended more readily for patients with active sacroiliac arthritis than for patients without this joint affected. Initiation of a TNFα inhibitor was recommended for patients with active sacroiliac arthritis who have received an adequate trial of NSAIDs and have high disease activity and features of poor prognosis (level C).(51,52) Initiation of a TNFα inhibitor was also recommended for patients who have received 3 months of methotrexate and have high disease activity, irrespective of prognostic factors, or moderate disease activity with features of poor prognosis, or 6 months of methotrexate and moderate disease activity without features of poor prognosis (level C).(51,52) Also recommended was initiation of a TNFα inhibitor for patients who have received 3 months of sulfasalazine and have moderate or high disease activity, irrespective of prognostic features, or 6 months of sulfasalazine and low disease activity with features of poor prognosis (level C).(51,52)

Systemic arthritis

The JIA category of systemic arthritis was divided into two treatment groups: active systemic features and active arthritis. The appropriate treatment of patients with concurrent active systemic features and active arthritis may be expected to incorporate elements of both sets of recommendations.

Options for the treatment of systemic arthritis appear to be increasing.

Systemic arthritis with active systemic features (and without active arthritis)

The definitions of disease activity and features of poor prognosis for this treatment group are listed in Table 4. A diagram of the overall treatment strategy is shown in Figure 3. These recommendations are not meant to apply to patients with clinical and laboratory evidence of macrophage activation syndrome that warrants specific modification of therapy. Life-threatening clinical scenarios (e.g., cardiac tamponade) may warrant deviation from these recommendations.

NSAID monotherapy—The use of NSAID monotherapy is appropriate during the clinical evaluation of possible systemic arthritis. The following recommendations apply to patients who have been diagnosed with systemic arthritis. The initiation (or continuation) of NSAID monotherapy was uncertain for patients with active fever. Initiation of NSAID monotherapy was inappropriate for patients with active fever and physician global assessment of overall disease activity (MD global) of ≥7 of 10 (level D). Continuation of NSAID monotherapy for a duration greater than 1 month was inappropriate for patients with active fever (level C).(53)

Systemic glucocorticoids—Owing to a near complete lack of published evidence, specific systemic glucocorticoid doses or routes of administration have not been determined. Initiation of systemic glucocorticoids (with or without additional concurrent therapy) was recommended as initial therapy for patients with active fever and MD global of ≥7 (level D). Initiation of systemic glucocorticoids following up to 2 weeks of NSAIDs was recommended for all patients with active fever (level C).(53,54)

Anakinra—Initiation of anakinra was recommended for all patients with active fever and features of poor prognosis, irrespective of current therapy (level C).(55) Initiation of anakinra was recommended for all patients who sustain or develop active fever while receiving systemic glucocorticoids (level C).(55-58)

Calcineurin inhibitors—Initiation of calcineurin inhibitors for patients with active fever and without active arthritis was uncertain for initial management.

Intravenous immunoglobulin—Initiation of intravenous immunoglobulin for patients with active fever and without active arthritis was uncertain for initial management.

Methotrexate—Initiation of methotrexate was inappropriate for initial management of patients with active fever and without active arthritis (level B).(32)

Thalidomide—Initiation of thalidomide for patients with active fever and without active arthritis was uncertain for initial management.

Systemic arthritis with active arthritis (and without active systemic features)

The definitions of disease activity and features of poor prognosis for this treatment group are listed in Table 5. A diagram of the overall treatment strategy is shown in Figure 4.

NSAID monotherapy—Initiation of NSAID monotherapy (with or without glucocorticoid joint injections) was recommended for patients with low disease activity without features of poor prognosis (level B).(23) It was presumed that most patients with newly diagnosed systemic arthritis would have received NSAIDs during their diagnostic evaluation. Continuation of NSAID monotherapy (without systemic therapy) for a duration greater than 1 month was uncertain for patients with any level of disease activity, irrespective of poor prognostic features (level D).

Methotrexate—Initiation of methotrexate was recommended for all patients with active arthritis following 1 month or less of NSAID monotherapy (with or without glucocorticoid joint injections), irrespective of poor prognostic features (level B).(40,79)

Anakinra—Initiation (addition) of anakinra was recommended for patients who have received methotrexate and who have moderate or high disease activity, irrespective of features of poor prognosis (level C).(55-59) Initiation of anakinra was also recommended for patients who have received methotrexate and a TNFα inhibitor or methotrexate and abatacept and have high or moderate disease activity, irrespective of poor prognostic factors (level C).(55-58) The initiation of anakinra for the treatment of arthritis may be less appropriate later in the disease course compared to nearer to the onset of disease.

TNFα inhibitor—Initiation (addition) of a TNFα inhibitor was recommended for patients who have received 3 months of methotrexate and have moderate or high disease activity, irrespective of features of poor prognosis (level B).(39,40) It may be appropriate to switch therapy from anakinra to a TNFα inhibitor for patients with moderate or high disease activity, irrespective of features of poor prognosis (level D). However, concern was expressed regarding possible unmasking of latent systemic disease activity when discontinuing anakinra.

Abatacept—Initiation of abatacept was recommended for patients who have received methotrexate and a TNFα inhibitor and have high disease activity, irrespective of features of poor prognosis, or have moderate disease activity and poor prognostic features (level B).(47)

Calcineurin inhibitors—Initiation of calcineurin inhibitors was inappropriate for patients with active arthritis and without active systemic features (level C).(60,61)

  •  
    Table 1: Features of poor prognosis and disease activity for a history of arthritis of 4 or fewer joints
  •    
  •  
    Table 2: Features of poor prognosis and disease activity for a history of arthritis of 5 or more joints
  •    
  •  
    Table 3: Feature of poor prognosis and disease activity for active sacroiliac arthritis
  •    
  •  
    Table 4: Features of poor prognosis and disease activity for systemic arthritis with active systemic features (and without active arthritis)
  •    
  •  
    Table 5: Features of poor prognosis and disease activity for systemic arthritis with active arthritis (and without active systemic features)
  •    
  •  
    Table 6: Summary of recommendations for medication safety monitoring
  •    
  •  
    Figure 1: Treatment recommendations for patients with a history of arthritis of 4 or fewer joints. To view this figure, please refer to the PDF file.
  •    
  •  
    Figure 2: Treatment recommendations for patients with a history of arthritis of 5 or more joints. To view this figure, please refer to the PDF file.
  •    
  •  
    Figure 3: Treatment recommendations for patients with systemic arthritis and active systemic features (and without active arthritis). To view this figure, please refer to the PDF file.
  •    
  •  
    Figure 4: Treatment recommendations for patients with systemic arthritis and active arthritis (and without active systemic features). To view this figure, please refer to the PDF file.
  •    

    Safety monitoring

    NSAID monitoring—Measurement of serum creatinine, urinalysis, complete blood cell count, and liver enzymes was recommended prior to or soon after the initiation of treatment with routine NSAIDs (level D). Periodic repeat measurements of serum creatinine, urinalysis, complete blood cell count, and liver enzymes were recommended approximately twice yearly for patients receiving chronic daily NSAIDs and approximately once yearly for patients receiving NSAIDs routinely (e.g., 3 to 4 days per week) (level D).

    Methotrexate monitoring—Measurement of serum creatinine, complete cell blood count, and liver enzymes was recommended prior to initiation of methotrexate (level D). Shortly after initiation of methotrexate, repeat measurements of serum creatinine, complete blood cell count, and liver enzymes were recommended. No single preferred monitoring strategy was recommended. In general, it is recommended laboratory measurements approximately 1 month after initiating methotrexate and then approximately 1 to 2 months after any subsequent increase in methotrexate dose (level D). Repeat measurements of serum creatinine, complete blood cell count, and liver enzymes were recommended approximately every 3 to 4 months for patients receiving a stable dose of methotrexate with no recent history of abnormal laboratory monitoring results (level C).(62,63) The laboratory measurements should be obtained 1 to 2 days prior to the scheduled weekly dose of methotrexate. In response to liver enzyme elevation of as much as 2 times the upper limit of normal, either no specific action or rechecking liver enzymes at a shorter interval was recommended. In response to liver enzyme elevation more than 2 times the upper limit of normal, decreasing the dose of methotrexate or temporarily withholding methotrexate administration was recommended. If liver enzymes remain at levels more than 3 times the upper limit of normal following a decrease in the methotrexate dose, discontinuation of methotrexate was recommended (all recommendations are level C).(62-65)

    TNFα inhibitor monitoring—Measurement of complete blood cell count, liver enzymes, and serum creatinine was recommended prior to initiation of TNFα inhibitors and approximately every 3 to 6 months thereafter for patients who continue to receive TNFα inhibitors (level D).

    Tuberculosis screening—Obtaining Mantoux purified protein derivative skin testing for tuberculosis was recommended prior to initiation of TNFα inhibitors for all patients (level C).(66) Repeat testing approximately once yearly thereafter was recommended for all patients who continue to receive TNFα inhibitors (level D). The appropriateness of interferon-γ release assays for detecting tuberculosis was not evaluated. The appropriateness of tuberculosis testing prior to the initiation of biologic agents other than TNFα inhibitors was not evaluated.

    Hepatitis B and hepatitis C screening—Antibody testing for infection with hepatitis B or hepatitis C prior to initiating methotrexate or TNFα inhibitors was recommended for patients with risk factors for infection (level D).



    Mehrnoush Hassas Yeganeh MD
    Assistant Professor, Paediatric Rheumatologist, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    *Corresponding Author
    mehrnoushyeganeh@gmail.com

       

    Shokouh Hashemi
    Shahid Beheshti University of Medical Sciences, Tehran, Iran
    shokuhhashemi@yahoo.com

       

    Neda Zafari
    Shahid Beheshti University of Medical Sciences, Tehran, Iran
    nedazafari@gmail.com

       

    Mahsa sardari
    Shahid Beheshti University of Medical Sciences, Tehran, Iran
    msnia134@yahoo.com

     
     

    Acknowledgements:
    None declared.

     
     

    Financial disclosure:
    None declared.

     
     

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