Based on the results of several Phase 2 and Phase 3 studies (two of which will be summarized below), the FDA has approved tofacitinib, at a dose of 5mg twice daily, for the treatment of RA in adults with moderate to severe disease, who have had an inadequate response to, or are intolerant of, methotrexate.  It can be used as monotherapy or in combination with methotrexate. It is not to be used in combination with other potent immunosuppressive medications or biologic agents.

RA patients clearly demonstrated a clinical response with tofacitinib compared to placebo in these trials with improvement in the number of painful and swollen joints. However, tofacitinib did not receive a prescribing indication from the FDA for the prevention of radiographic progression, based on the available data.

Inhibition of JAK signaling is a potent pathway to interrupt, and there are some important side effects to be aware of with this drug. Notably, severe infections, including opportunistic infections, were noted in the treatment groups. However, infection rates were similar to those seen with other biologic DMARDs. All patients should be screened for latent TB prior to starting tofacitinib. Herpes zoster infections occurred at a higher rate in individuals treated with tofacitinib than placebo. This rate of herpes zoster was higher than what has been observed in other biologic DMARD studies, and while not indicated on the label, we believe that consideration should be given to vaccinating patients prior to the initiation of tofacitinib. Live vaccines (such as the herpes zoster vaccine) should not be administered to patients taking tofacitinib. Hematologic abnormalities (neutropenia, lymphopenia, and anemia) were observed with tofacitinib and need to be routinely monitored for during treatment. Monitoring of transaminases, lipids, and creatinine also should be done regularly, as abnormalities in all of these laboratory parameters were observed during the trials.  Dose reduction of tofacitinib is required for patients taking CYP3A4/CYP2C19 inhibitors (i.e. ketoconazole or fluconazole) due to increased levels of the drug.

The addition of a powerful oral molecule with biologic-like efficacy on signs and symptoms of RA to the armamentarium of treatments we have to offer patients suffering with RA is an exciting prospect. However, the oral delivery of this drug should not be taken to imply increased safety or less potency than injectable or infusible biologic therapies.

Two important studies evaluating the safety and efficacy of tofacitinib for the treatment of rheumatoid arthritis were published recently in the New England Journal of Medicine. These studies are summarized below:

• Fleischmann R, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.  NEJM 2012;367:495-507

Methods:

Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) who had failed (because of lack of efficacy or side effects) at least one other RA therapy (biologic or nonbiologic DMARD) were eligible for inclusion. The study design was a randomized, double-blind, placebo-controlled, parallel-group trial. Participants were randomized to one of four possible treatment groups for a total of 6 months. 1) Tofacitinib 5mg twice daily x 6 months; 2) tofacitinib 10mg twice daily x 6 months; 3) placebo x 3 months followed by tofacitinib 5mg twice daily x 3 months; 4) placebo x 3 months followed by tofacitinib 10mg twice daily x 3 months.  Comparisons were made between placebo and tofacitinib at 3 months on three primary endpoints: ACR20 response (at least 20% reduction from baseline in the number of tender and swollen joints + 20% improvement in ≥3/5 of the following: patient pain assessment, disability, CRP, global disease activity by patient, global disease activity by physician), change in HAQ-DI (disability index), and DAS28-4(ESR) score <2.6. The DAS28-4(ESR) is a composite index of 4 weighted variables (# of tender joints from 28-joint count, # swollen joints from 28-joint count, ESR, patient’s global assessment of disease activity). Adverse events were also collected and analyzed compared to placebo.

Results:

611 RA patients were randomized for this study. 122 received placebo for the first 3 months. 243 received 5mg tofacitinib twice daily, and 245 received 10mg tofacitinib twice daily. The patients had a mean age of 50-52 years, and a mean RA disease duration of 7.7-8.6 years. After 3 months, 59.8% in the 5mg tofacitinib group, 65.7% in the 10mg tofacitinib group, and 26.7% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was not a significant difference between the groups by the outcome DAS28-4(ESR), however there was by 6 months. There were more adverse events in the tofacitinib groups compared to placebo. 6 patients had serious infections. 54% had adverse events with the most common being upper respiratory tract infections, headaches, and diarrhea. Lab abnormalities that occurred more frequently among the tofacitinib groups were neutropenia, elevated transaminases, elevated LDL cholesterol, and serum creatinine.

Conclusions:

Tofacitinib as monotherapy, compared with placebo, reduced signs and symptoms of RA and improved function among adults who had failed a previous DMARD. However, the endpoint for remission (DAS28-4(ESR)<2.6) was not met. There were more adverse events in the tofacitinib groups compared to placebo with infections, including serious infections, topping the list. 

• Van Vollenhoven R, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.  NEJM 2012;367:508-519  The ORAL Standard trial

Methods:

Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) despite receiving treatment with 7.5-25mg of methotrexate weekly  were eligible for inclusion. Important exclusion criteria were current treatment with other anti-rheumatic agents (including biolgoics), prior treatment with adalimumab, lack of response to previous anti-TNFα agent, or current infection.  The study design was a randomized, phase 3 clinical trial. Participants were randomized to one of 5 possible treatment. 1) Tofacitinib 5mg twice daily; 2) tofacitinib 10mg twice daily; 3) 40mg adalimumab every other week; 4) placebo for 3 or 6 months followed by tofacitinib 5mg twice daily; 4) placebo for 3 or 6 months followed by tofacitinib 10mg twice daily. If patients who received placebo did not have a 20% reduction in swollen and tender joints after 3 months they were randomly assigned to 5 or 10mg of tofacitinib. After 6  months, all patinets on placebo were switched to tofacitinib.

The primary endpoints were: ACR20 response , HAQ-DI, and DAS28-4(ESR) score <2.6. Adverse events were also collected and analyzed compared to placebo. The study lasted 12 months.

Results:

717 RA patients were randomized for this study. 56 received placebo and 5mg tofacitinib. 52 received placebo and 10mg tofacitinib. 204 received 5mg tofacitinib twice daily. 201 received 10mg tofacitinib twice daily. 204 received 40 mg adalimumab every other week. The patients had a mean age of 52-55 years, and a mean RA disease duration of 6.9-9.0 years. After 6 months, 51.5% in the 5mg tofacitinib group, 52.6% in the 10mg tofacitinib group, 47.2% in the adalimumab group, and 28.3% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was also significantly more patients in the treatment groups compared to placebo who reached the  DAS28-4(ESR) outcome.

Adverse events in the treatment groups included neutropenia, elevated transaminases, elevated LDL cholesterol, elevated serum creatinine, and low hemoglobin. Other adverse events included primarily infections. The rates of serious adverse event in the first three months were higher in tofacitinib groups than placebo or adalimumab. This included 2 cases of pulmonary tuberculosis.

Conclusions:

Tofacitinib in combination with methotrexate was superior to placebo to treat the signs and symptoms of RA. In this study, the efficacy of tofacitinib at 12 months was numerically similar between all treatment groups, including adalimumab.

Methods:

Patients were included in the study from the Arthritis Conditions Health Effects Survey 2003-2005. This is a cross-sectional telephone survey of US adults age ≥45 years with self-reported doctor-diagnosed arthritis. Anxiety and depression were assessed with the Arthritis Impact Measurement Scale which is comprised of 12 questions (6 for anxiety and 6 for depression) and also measures the frequency of symptoms. The average subscale value for each condition (anxiety, depression) was calculated. The presence of the condition was defined as a mean value ≥4. Additional variables assessed during the phone interview included sociodemographic characteristics, arthritis symptoms, physical function, and modifiable health and self-management behaviors.

Results:

11.5 million adults with arthritis reported anxiety and 6.6 million reported depression. 5.5 million reported having both. Most respondents with depression also had anxiety (84%). Anxiety was highest among respondents age 45-64 years, had severe joint pain, and reported only ‘good’ or ‘poor/fair’ health. Anxiety was also high among those who had ‘no or moderate confidence in their ability to engage in moderate physical activity at least 3 times/week’. Depression was most frequently reported among those who had difficulty bathing or dressing themselves (48%). It was also common among those unemployed or unable to work, Hispanics, those with severe fatigue, those who had no/low confidence in their ability to manage their arthritis, and those who had no confidence in their ability to engage in moderate physical activity at least 3 times per week. Respondents with both anxiety and depression were most likely to seek help (57.1%). Help was sought from their doctor (82-83%), family/friends (45-46%), therapist/counselor (43-46%), and other support systems. But 55% of arthritis patients with anxiety, depression or both had not soughtany help in the past year despite their mood symptoms.

Conclusions:

One-third of the respondents in this survey of US adults with arthritis had anxiety, depression, or both. More than half of these individuals had not sought help for their mental health condition in the past year. Disability and limitations (even perceived limitations) in physical activity were closely correlated with depression and anxiety as well.

Editorial Comment:

Addressing mental health issues that frequently accompany chronic diseases, such as arthritis, are a critical component of the comprehensive care of our patients. Treatment can be complex and involve additional providers, medications, and support networks. It is worrisome that more than half of the patients with depression and anxiety have not sought help nor for these conditions, emphasizing the need for the health care community to recognize these entities and implement appropriate screening. We cannot expect our patients to follow our recommendations for exercise, medication compliance, and pain management until these important issues are also addressed.

Methods:

Pooled data from patients who had undergone screening for TB with both the IGRA and PPD test while enrolled in 1 of 5 phase III randomized placebo-controlled clinical trials for golimumab were included in these analyses. The 5 pooled studies included patients with RA (early and previously treated with TNFα inhibitors), psoriatic arthritis, and ankylosing spondylitis. These were international trials, so a wide range of patients were represented. Patients were screened for eligibility in the trials with the same criteria which included 3 TB screening tests: standard PPD, IGRA, and a chest x-ray. Analyses for this study included concordance between the PPD and IGRA results overall, by known BCG vaccination status, and by geographic region. Logistic regression was also completed to evaluate for factors associated with the screening test results.

Results:

2303 patients with inflammatory arthritis were included in these analyses from the 5 pooled trials with a median age of 49 years. Almost half were from North America (41.8%) and were receiving corticosteroids (43.4%, median dose 5mg/day). 788 patients had received the BCG vaccine, and 255 had unknown BCG status. 317 patients (13.8%) began treatment for latent TB because of this testing. 99.1% of the patients had both IGRA and PPD testing. 13.8% of all 2282 patients had at least one TB screening test that was positive. 9.4% had positive PPDs, and 7.0% had positive IGRA, and 2.6% were positive on both. 1.8% had indeterminate results on IGRA. Among the patients positive by IGRA, 36.9% were also positive by PPD. Among the patients with a positive PPD, 27.4% were also positive by IGRA. The kappa coefficient for agreement between the 2 tests was 0.22 (95% CI 0.157-0.279). Among those with a known history of BCG vaccination, 15.2% had positive PPD testing compared to 9.1% with positive IGRA testing (p=<0.001). Factors associated with a positive IGRA by logistic regression were age (≥65 years) and geographic areas outside of North America. Individuals who received the BCG vaccine had a higher odds of a having a positive PPD than those who did not receive the vaccine (OR 2.47, 95% CI 1.71-3.55).

Conclusions:

With a kappa coefficient of 0.22 there was considerable discordance in the rate of positive results between PPD and IGRA testing. Among those with BCG vaccine, the rate of PPD positivity was significantly greater than IGRA positivity suggesting this may represent some false positive results with PPD in this population. These data suggest IGRA may provide greater specificity for latent TB among those with inflammatory arthritis than PPD.

Editorial Comment:

Screening for latent TB in patients with inflammatory arthritis who will be starting TNFα inhibitors is important to prevent complications of TB-reactivation. However, currently there is no ‘gold standard’ for the diagnosis of latent TB. PPD is a good option as it is inexpensive, easy to administer, and has been used as a screening test for over a century. But many of the short-comings of PPD, which are reviewed in this article, are important in a population with inflammatory arthritis – such as inaccuracies in immunosuppressed patients (leading to false-negative results) and those who have received BCG vaccination (leading to false-positive results). Hence, having another option for screening, such as IGRA, is a meaningful advance. Unfortunately, without a definitive ‘gold standard’ we are left having to make inferences about the performance of the IGRA test; hence results should be interpreted with caution.

Methods:

Adult female participants with RA or SLE in the National Data Bank for Rheumatic Diseases were mailed a comprehensive reproductive questionnaire. This questionnaire asked participants about their reproductive history (ever pregnant, number of pregnancies, number of miscarriages, etc) and if they had a personal history of infertility. Additional questions were included that addressed issues of reproductive intent. Based on the participants’ responses, women were categorized as: A) those who had fewer children than they had intended; B) those who had the same number of children as they had intended; C) those who had completed childbearing at the time of diagnosis.

Results:

578 (68%) RA patients and 114 (69%) SLE patients completed the reproductive questionnaire. Women with SLE were younger at age of symptom onset than RA (35.7 vs 38.4 years, p=0.07) and younger at age of reproductive questionnaire completion (53.8 vs 58.6 years, p<0.01). The percentage of women in Group A, B, or C was similar for RA and SLE (A: 21% RA, 25% SLE; B: 16% RA, 14% SLE; C: 63% RA, 60% SLE). For both RA and SLE, women who developed symptoms of their disease prior to the completion of having children ended up with fewer children than they had planned. The mean number of pregnancies, children, and terminations was similar between RA and SLE women; however, SLE women had a higher rate of miscarriages. Among women with RA, those in Group A had on average 1 less pregnancy and 1 less child than women in Group B or C. RA women in Group A, as expected, reported the highest infertility rate (42%) with causes including ovulatory dysfunction, unexplained, and endometriosis. However, 58% of RA women in Group A did not report infertility but had fewer pregnancies and children than they had hoped. Reasons reported for this discrepancy included: concern about their ability to care for children; concern that their disease or medications would harm the baby; and concern their children would develop RA. Among women with SLE, 21.7% of the pregnancies ended with miscarriage. Among women with RA, older age at diagnosis was associated with a higher number of pregnancies and infertility – and reporting more reasons for avoiding conception was associated with fewer pregnancies. Infertility, age of SLE onset, and miscarriage did not impact the number of pregnancies or live births for women with SLE.

Conclusions:

More than a half of the women with RA and SLE in this cohort diagnosed with their disease prior to completing child bearing had fewer children than they originally planned. Contributing factors include reported infertility (particularly among RA), pregnancy loss (particularly in SLE), and concerns about the impact of their autoimmune disease on their children.

Editorial Comment:

Decisions about family planning are very personal and are an important part of the overall health care of our female patients with RA and SLE. As a health care community, it is critical we address patients’ concerns about fertility and family in the context of their inflammatory disease. This study clearly demonstrates that our patients are dealing with these issues, and it is our responsibility to educate our patients so they can make well-informed decisions based on data and facts and not fears or fallacies. Infertility in RA and SLE is an understudied area that deserves more attention to understand causes and optimal management.     Rebecca L Manno, MD, MHS

Methods:

All patients (adult RA) who participated in the original RCT were eligible for inclusion. These patients had been randomized either to receive supervised high-intensity resistance exercise (for 24-weeks) or home-based low-intensity range of movement exercise. Of note the original RCT did not continue to provide an exercise program for participants outside the 24-weeks of the original study. Follow up (3 years post-study) measures included: body composition by DEXA, knee strength, functional measures (20-second chair stand, 20-second arm cur., 50-foot walk), and RA disease activity (DAS28). Participants were asked about their physical activity, medications, diet, and leisure activities as well.

Results:

18 RA patients from the original study (n=28) participated in the 3 year follow up measures (n=9 intervention; n=9 controls). None of the subjects were performing high-intensity progressive resistance training at follow up or any other form of regular high-intensity exercise. Body weight was unchanged in the group who previously participated in the exercise program, but the gains in lean made during the study were lost. There was some preservation of body composition change regarding loss of fat mass. Gains in gait speed did persist among the exercise group resulting in 66% retention in walking speed improvements for those who had exercised compared to those in the control group.

Table 1.

Conclusions:

Changes in fat mass and improvements in gait speed achieved through a 24 week program of high-intensity resistance exercise in RA patients were sustained up to 3 years in follow up, even without continuing the exercise program. Gains in lean mass and strength measures, however, did not persist. Importantly, no patients continued to participate in any structured resistance exercise training programs.

Editorial Comment:

This 3-year follow up of resistance exercise in patients with RA puts real data behind the commonly used term “use it or lose it.” RA patients made impressive gains in lean muscle, fat loss, strength and function (as evidenced by gait speed) with resistance exercise – only to lose most if it by stopping exercising altogether with the end of the study. Further investigation into the barriers that RA patients face regarding participation in routine exercise programs (is the problem access? pain? cost? time?) needs to be conducted so we can help our patients overcome these obstacles. Exercise is an important part of the overall treatment of RA due to the many benefits to joint, muscle, and overall health.

For more information on how to use this app go to: www.dkbmed.com/apps/RAVE for a video tutorial.

Key features include:

The PATIENT CHART: an interactive single-screen overview of each patient featuring key lab results, prescribed meds, reported side effects, and case notes. The Patient Chart updates each time new information is added and can be emailed or printed directly from the app.

COMORBIDITY CHECKLIST: an interactive checklist of common comorbid conditions to assist coordination of treatment between the rheumatologist and primary care physician for safe and effective patient care. Input into the RAVE Mobile Comorbidity Checklist automatically updates the Patient Chart.

DIAGNOSTIC CALCULATOR: automatically calculates and reports each patient’s classification score according to the 2010 ACR/EULAR Classification System and records it to the Patient Chart. The ACR/EULAR criteria set includes joint involvement, serology, acute-phase reactants, and duration of symptoms.

DAMs: provides RA disease activity measurement (DAM) calculators to monitor treatment efficacy, with results automatically updated to the Patient Chart. Calculators are included for CDAI, SDAI, DAS28-CRP and DAS28-ESR, as well as a historical-tracking feature to monitor patient changes over time.

RAVE MEDICATION GUIDE: documents each patient’s medications and provides a handy point-of-care resource for commonly prescribed therapeutic agents. Includes information on common side effects as well as recommendations on baselines, monitoring intervals, special considerations, and REMS. Individual patient side effects can be entered and saved in the Patient Chart.

RAVE Mobile is supported by educational grants from Abbott Laboratories, Centocor Ortho Biotech Services LLC, Genentech, Inc., Pfizer, Inc.

We hope you find version 1.0 of this application useful and look forward to hearing your comments and suggestions for future enhancements. 

Methods

This was a prospective, randomized, double-blind, double-dummy phase 3 study of patients age 12-75 years with active class III, IV, or V lupus nephritis who successfully responded to induction therapy with mycophenolate mofetil or cyclophosphamide. Patients were then randomly assigned to mycophenolate mofetil or azathioprine for maintenance therapy and followed for 36 months. The primary end point was time to treatment failure. Treatment failure was defined as death, development of end-stage renal disease, sustained doubling of creatinine, renal flare, or the need for additional therapy in the context of lupus nephritis.

Results

227 patients with lupus were randomly assigned to receive maintenance treatment with mycophenolate mofetil (n=116) or azathioprine (n=111). After 36-months, 73 patients in the mycophenolate group (63%) and 54 patients in the azathioprine group (49%) completed the study. Regarding the primary end point, time to treatment failure, there were fewer patients in the mycophenolate group (16.4%) compared to the azathioprine group (32.4%) and this was statistically significant [HR for treatment failure 0.44, 95% CI 0.25, 0.77]. The overall number of adverse events was similar between the two groups (p=0.68) with the most common being infection. A higher proportion of patients in the azathioprine group had adverse events which led to drug withdrawal (39.6%) compared to the mycophenolate group (25.2%).

Conclusions

Mycophenolate mofetil is superior to azathioprine for the maintenance of renal remission and the prevention of renal relapse in patients with lupus nephritis who responded to induction therapy (with either cyclophosphamide or mycophenolate mofetil).

Editorial Comment

Although this study demonstrates superiority of mycophenolate mofetil compared to azathioprine for maintenance of renal remission, it is important to recognize the study population in whom these data can be applied. Notably, this is a population of lupus patients who responded to induction therapy. Further, the study was not powered to note particular differences in subgroups. The subgroups which may be of particular interest in future investigations are the differential efficacy of mycophenolate and azathioprine among racial groups (Caucasian vs African American vs Asian, etc) and if there is a differential response among t

(Mizelle, K. & Fontaine K.R. 

Fibromyalgia has no cure and the management of this condition is difficult. Both pharmacological and non-pharmacological approaches are considered essential to assist these patients in better managing their illness. Exercise also has been shown to improve symptoms and quality of life in multiple studies. However, the pain, stiffness, and fatigue that characterized fibromyalgia make exercising consistently a challenge. In this review article, the potential value of exercise and physical activity as treatment for patients with fibromyalgia is described.

Methods

The investigators reviewed the studies that have evaluated the effects of exercise and various forms of physical activity (such as yoga and tai chi) on symptoms, fitness, and quality of life in persons with fibromyalgia.

Results

Based on a review of 34 exercise studies, there was moderate-quality evidence for the short-term effectiveness of aerobic exercise for the treatment of fibromyalgia. Aerobic exercise at moderate intensity levels produced positive effects on global well-being and physical function.  The effects of aerobic exercise on pain and tender points were variable but suggestive of benefit. Evidence for the effectiveness of aerobic exercise is limited with regard to stiffness, fatigue, and depression. Small studies suggest beneficial effects of strengthening exercise on pain, global well-being, tender points, and depression. However, larger studies need to be conducted before strengthening exercise can be recommended for fibromyalgia. Increasing physical activity throughout the normal course of the day (lifestyle physical activity), flexibility exercise, tai chi, yoga, and pool-based exercise have also been shown to produce benefits for people with fibromyalgia.

Conclusion

Exercise and various forms of physical activity can play an important role in the treatment of fibromyalgia. Aerobic exercise has been shown to produce moderate benefits on functioning and well-being, while the evidence for the effectiveness of strength training, flexibility training, yoga, and tai chi is beginning to be accumulated.  Given the value of exercise and physical activity for fibromyalgia, the central issue is finding ways to assist people with fibromyalgia to exercise consistently enough to derive maximal benefits.

Editorial Comment

Although these approaches are promising in helping people to better manage their fibromyalgia, tolerance for the exertion associated with increased levels of physical activity is a critical issue. The slow and gradual introduction of physical activity and/or traditional exercise may minimize the chances of worsening fibromyalgia symptoms. It is also important for people with fibromyalgia to understand that they are capable of becoming more physically active.  Health professionals play a crucial role in counseling and preparing people with fibromyalgia to become more physically active and helping them to manage the potential obstacles and setbacks as they strive to incorporate elevated levels of physical activity into their lives.

Methods:

Adult patients with active RA (≥ 10 swollen and ≥ 12 tender joints and CRP ≥ 0.8 mg/dL) despite more than 3 months of treatment with methotrexate (at doses ≥ 15mg/week) were randomized to receive abatacept by subcutaneous injection (after intravenous loading dose 10mg/kg on day 1; then 125 mg subcutaneous on day 1 and 8; then 125mg subcutaneous weekly) or intravenous infusion (10mg/kg on day 1, 15, 29; then monthly). The study design was randomized, double-blind, double-dummy study; therefore patients in both groups received subcutaneous or intravenous placebo, as appropriate.  The study was powered to be a non-inferiority comparison. The primary endpoint was ACR 20 response at month 6. ACR 50, ACR 70, and HAQ-DI (also at month 6) were secondary endpoints. Safety assessments were completed regularly for both groups and included injection site reactions and infusion reactions.

Results:

1457 RA patients were randomized for treatment with abatacept (n=736 subcutaneous; n=721 intravenous). The proportion of patients achieving an ACR 20 response at Month 6 was 76.0% (95% CI 72.9, 79.2) for the group receiving subcutaneous abatacept and 75.8% (95% CI 72.6, 79.0) for the group receiving intravenous abatacept. Similarly, the ACR 50 and 70 responses were comparable between the two groups. The proportion of patients in each group with improvements in HAQ-DI was comparable (68.2% subcutaneous vs 63.8% intravenous). The safety profile was also similar between the two groups. The most commonly reported adverse events in either group were headache, nasopharyngitis, upper respiratory infections, and gastrointestinal symptoms. No patients discontinued the drug due to serious infections in the subcutaneous group but four patients did in the intravenous group; although overall the frequency of infections was comparable between the two groups and were generally mild or moderate. Injection site reactions were reported in 2.6% of patients in the subcutaneous group and 2.5% of the patients receiving placebo. All injection site reactions were mild or moderate and did not result in discontinuation of the drug.

Conclusions:

This non-inferiority study comparing the subcutaneous and intravenous delivery methods of abatacept found them to be equally efficacious for the treatment of RA in patients with an inadequate response to methotrexate. Importantly, the safety profile was similar for both groups and the overall incidence of injection site reactions was low.

Editorial Comment:

Abatacept is the first biologic to be available in both subcutaneous and intravenous formulations. Infusions can be a logistical challenge for some patients, particularly those with full-time employment, child-care responsibilities, and elderly with poor mobility and transportation limitations. Self-administered subcutaneous injections can circumvent some of these issues. The selection of a biologic agent for the treatment of RA is ultimately a joint decision between the patient and provider with consideration of several issues including disease severity, response to previous treatments, and patient comfort with drug administration (injection vs infusion). The FDA approval of a subcutaneous form of abatacept allows providers to have more options when considering treatment for RA, and this can only help patients in the long run.

Methods:

Adult patients with RA and a DAS28 of at least 3.2 started on treatment with adalimumab at 40mg every other week (+/- concomitant synthetic DMARD therapy) were enrolled in this study. Disease activity was measured by DAS28 at baseline and at 9 time points over three years (while on adalimumab). Minimal disease activity was defined as a DAS28 <3.2 at all consecutive measurements after a certain time point. Remission was defined as DAS28 <2.6 at all consecutive measurements after a certain time point. Discontinuation of adalimumab or dropout of the study was also an outcome parameter. Trough adalimumab serum concentrations and antidrug (anti-adalimumab antibodies) were measured at the same time points as DAS28.

Results:

272 patients were enrolled in the study, and 55% completed the entire follow up time of 3 years. Anti-adalimumab (antidrug antibodies) were detected in 76 (28%) patients, the majority of which developed these antibodies during the first 28 weeks of treatment (67%). Of the patients with anti-adalimumab antibodies, 38% discontinued participation during follow up because of treatment failure, 10% for adverse events, 3% because of treatment failure and adverse events combined, and 12% for other reasons. Patients with anti-adalimumab antibodies more often discontinued study participation compared to those who were anti-adalimumab antibody negative, even after adjustment for methotrexate use, number of previous DMARDs, and CRP (HR 3.0; 95% CI 1.6-5.5). Patients with anti-adalimumab antibodies had a higher DAS28 score at all time points compared with anti-adalimumab antibody negative patients, even after adjustment for ESR, MTX dose, and age (0.4; 95% CI 0.2-0.6). Patients with anti-adalimumab antibodies were less likely to achieve sustained minimal disease activity (HR 3.6, 95% CI 1.8-7.2) and were less likely to achieve sustained remission (HR 7.1; 95% CI 2.1-23.4).

Conclusions:

In this study, the development of antidrug antibodies to adalimumab was associated with increased rates of discontinuation of treatment and increased disease activity. These antibodies were most likely to develop during the first 28 weeks of treatment.

Editorial Comment:

The immunogenicity of biologic agents is a well-established phenomenon, but the clinical implications of such are not clear. Gaining an understanding of how antidrug antibodies influence clinical response to a biologic agent can potentially have important ramifications in a RA patient’s treatment plan by influencing provider’s decisions to switch therapy. For example, extrapolating from these data, if a patient is showing a poor response to adalimumab and has developed anti-adalimumab antibodies, this may strongly influence the provider to swiftly switch to another agent. Further, the development of antidrug antibodies may explain why some patients develop a ‘tolerance’ to therapy, particularly with periods of drug discontinuation (and then re-initiation). We do not know why some patients develop antidrug antibodies and others do not. This is an important area of investigation, as understanding this process may allow us to tailor therapy at the time of drug initiation. Further investigation in this field is underway and exciting as we come closer to understanding how to optimally and efficiently treat RA.