s basic research on new targets for rheumatoid arthritis (RA) treatment continues, novel therapies move through phase II trials. Multiple approaches to therapy continue to be needed because RA and other related inflammatory diseases continue to progress in most patients despite additions to and switching of therapies. New drugs with different mechanisms of action can halt erosive effects for a time, thereby delaying disease progression.

Recent insights into the processes driving the autoimmune attack underlying RA have led to promising new treatments, many of which were presented at the 2012 European League Against Rheumatism (EULAR) Annual Congress in June.

Many of the &ldquo;new&rdquo; targets being tested are only new to these arthritis diseases and have been used in other therapeutic areas, most often in cancer patients. These include granulocyte-macrophage colonystimulating factor (GM-CSF) and transforming growth factor-beta agents, both familiar in the cancer world.

A summary of abstracts presented at the 2012 EULAR Annual Congress are presented here. Selections were chosen because they shed light on several emerging changes in treatment with targeted therapies.

Interleukin-20 appears to be a valid drug target in rheumatoid arthritis (RA), according to placebo-controlled trial results with a monoclonal antibody designed to inactivate the protein. However, the trial was small (67 patients), and results were affected by presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA).

In this phase II trial, across all 67 patients, the monoclonal antibody NNC0109-0012 reduced Disease Activity Scale- (DAS) 28 scores including C-reactive protein measurements (DAS28-CRP) by 0.88 points relative to placebo in 12 weeks of treatment. (

When the analysis was restricted to the approximately two-thirds of patients in both treatment groups who were positive for RF and ACPA, the mean DAS28-CRP scores declined by about 0.7 points in the placebo group versus 2.4 points with the study drug (

Interleukin-20 (IL-20) is secreted from synovial tissues, which also contain receptors for the cytokine. Studies in animal models of RA indicate that anti-IL-20 monoclonal antibodies relieve pain and inflammation and prevent joint erosion.

In the current trial, treatment was stopped at week 12 (except for methotrexate), but patients were followed and evaluated for an additional 13 weeks. During that time, the difference in responses in sero-positive patients was maintained, with only slight increases in DAS28-CRP scores in both groups from weeks 12 to 25.

&Scaron;enolt L, G&ouml;thberg M, Valencia X, et al. Efficacy and safety of NNC0109-0012 (anti-IL-20 Mab) in patients with rheumatoid arthritis: results from a phase 2A trial.

Stelara Investigated for Use in Psoriatic Arthritis

Study results presented at the 2012 EULAR Annual Congress indicated that ustekinumab (Stelara), an agent already used in psoriasis, may help ease swollen joints in patients with active psoriatic arthritis.

In the phase III PSUMMIT I study, treatment with the interleukin (IL)-12 and IL-23 inhibitor ustekinumab led to 20% improvements in the ACR20 criteria in 42.4% of patients receiving 45 mg and in 49.5% of patients receiving 90 mg, compared with 22.8% of patients treated with a placebo (

Psoriatic arthritisa deforming and debilitating arthritis characterized by inflammation of the synovium, enthesis, and periosteum&mdash;develops in approximately 10% to 15% of patients with psoriasis. Current treatment options include conventional disease-modifying drugs such as methotrexate and sulfasalazine, nonsteroidal anti-inflammatory drugs, and biologic TNF inhibitors; however, many patients have inadequate responses to these approaches.

Good results on skin involvement were expected because ustekinumab is already licensed and in clinical use for psoriasis. Researchers said that the real test in this trial was whether the treatment also worked in the joints, and the answer, at least in comparison with placebo, was that it did.

A 75% improvement in skin involvement was observed in 57.2% of patients receiving the 45-mg dosage and in 62.4% of patients receiving the 90-mg dosage, compared with 11% of those receiving placebo.

McInnes I, Kavanaugh A, Gottlieb AB, et al. Ustekinumab in patients with active psoriatic arthritis: results of the phase 3, multicenter, double-blind, placebo-controlled PSUMMIT 1 study.

Results of the first two head-to-head trials of biologic agents for RA were reported at the EULAR Congress in Berlin, Germany. According to news reports of the congress proceedings, these trials caused significant discussion both on and off the floor of the presentations.

Driven by regulatory requirements in Europe, drugs for RA and related conditions are increasingly being tested against other active agents in clinical trials, but the relevance of the results for clinical practice is a matter of debate, according to EULAR president Maxime Dougados, MD, of Ren&eacute; Descartes University in Paris, who is also an active researcher in the field.

With the caveat suggested by Dougados, the two head-to-head trials that follow offer new information that may or may not help in making prescribing decisions concerning choice of biologic agents for RA.

Tocilizumab (Actemra, Genentech) vs Adalimumab (Humira, Abbott) as Monotherapy for RA

Tocilizumab is an infused agent, currently indicated for the treatment of adult patients with moderatelyto- severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF inhibitors. It can be given with or without methotrexate.

Classified as a non-TNF biologic, tocilizumab is an interleukin 6 (IL-6) receptor monoclonal antibody. IL-6 is a pro-inflammatory cytokine produced by a variety of cell types, including T and B cells, lymphocytes, monocytes, and fibroblasts.

In this randomized, double-blind trial, tocilizumab was significantly more effective than adalimumab as monotherapy for patients with RA who were unresponsive to or unable to take methotrexate. Adverse events were similar between the two agents. In all efficacy measures, tocilizumab was higher than adalimumab.

Under current guidelines, most biologic drugs are not recommended as monotherapy in the US or Europe. Instead, a combination regimen with methotrexate or other conventional DMARDs is usually preferred. Nevertheless, in practice, a significant number of patients do receive biologics as single agents. Reasons vary: Some patients do not tolerate methotrexate well, or a copay issue might cause some to use a single agent only, or a patient&rsquo;s preference may favor taking a single drug.

The 24-week trial randomized 326 patients to either 8 mg/kg of tocilizumab by IV infusion every 4 weeks, or 40 mg of adalimumab, by subcutaneous injection every 2 weeks.

On the study&rsquo;s primary outcome measure, change in Disease Activity Scale-28 (DAS28) score from baseline, tocilizumab was clearly superior, with a decline in mean scores of 3.3 points versus 1.8 with adalimumab (

< .0001). The secondary efficacy endpoints of response rates in each study arm also favored tocilizumab (see Table 1).

Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy is superior to adalimumab monotherapy in reducing disease activity in patients with rheumatoid arthritis: 24-week data from the phase 4 ADACTA trial.

Abatacept (Orencia, Bristol-Myers Squibb) vs Adalimumab (Humira, Abbott)

The head-to-head trial of these two biologic therapies for RA resulted in a draw, according to many reports from the 2012 EULAR Annual Congress, where the data were presented. Multiple measures of clinical response in patients with early rheumatoid arthritis showed that the two biologic drugs were equally effective.

Abatacept is an anti-CD28 peptide that blocks T-cell activation, and adalimumab is the leading TNF inhibitor. The study&rsquo;s primary endpoint was efficacy after 1 year, the results of which were reported at the EULAR meeting. The study will continue for another 12 months. Study participants had had an inadequate response or relapse after treatment with methotrexate alone and had not yet received biologic therapy.

Both drugs were given with methotrexate, according to their currently approved labels. Abatacept was given by subcutaneous injection at 125 mg weekly; the adalimumab dosage was 40 mg every other week.

The study&rsquo;s primary endpoint was 20% reduction in symptoms by American College of Rheumatology criteria (ACR20) at 1 year. Response rates for for abatacept were 64.8%, and 63.4% for adalimumab, meeting the prespecified definition for abatacept noninferiority.

Rates of low disease activity (DAS28 score &le; 3.2) and remission (DAS28 <2.6) at 1 year were also virtually equal, according to Michael Schiff, MD, the researcher from the University of Colorado in Denver who served as the trial&rsquo;s lead investigator.

Compared with TNF inhibitors, abatacept has a reputation for relatively slow onset of action, but in the trial, responses over time tracked closely in the two study arms. At week 2, there was a statistically insignificant advantage for adalimumab in ACR20 response rates and DAS28 scores.

Eighty-five percent of patients on abatacept were rated as radiographic nonprogressors versus 89% of the adalimumab group. Rates of severe adverse events and serious infections were similar

Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: one year results from the AMPLE study.

Articles

Clinical Articles

As basic research on new targets for
rheumatoid arthritis (RA) treatment
continues, novel therapies move
through phase II trials.

News From EULAR 2012: New Drug Targets Emerge for RA

he Janus kinase ( JAK) molecule is an immunomodulating signal transduction agent, which has emerged as a new target for rheumatoid arthritis (RA) research. Four JAK enzymes have been identified: JAK1, 2, 3, and TYK2.

All four enzymes are critical components of signaling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in patients with RA. Cytokines such as interleukin-6, 12, and 23 signal through the JAK pathway; these particular cytokines have already been clinically validated as therapeutic targets in inflammatory diseases.

Several agents for RA that target the JAK enzymes are now in development, including:

Tofacitinib: inhibits JAK1, JAK2, and JAK 3

Baricitinib: inhibits JAK1 and JAK2, and its manufacturer describes it as &ldquo;JAK3-sparing&rdquo;

Tofacitinib (Pfizer) Inhibits JAK1, JAK2, and JAK3: Phase III data

Tofacitinib is likely to be the first oral biologic agent to be approved in the US for treatment of patients with RA. Tofacitinib is an oral JAK inhibitor, now with phase III data under review. In the pivotal trials, both the 5-mg twice-daily dose and the 10- mg twice-daily dose of tofacitinib were superior to placebo on three primary efficacy endpoints.

However, while the FDA Advisory Board in May 2012 moved the drug forward with a highly positive 10 to 0 vote on its efficacy data, the vote on safety data was somewhat troubling at 7 positive votes, 2 negatives, and 1 abstention. The negative reviews were most affected by a perceived increased risk of malignancy in the higher-dosage arm of the trial, with one reviewer saying that it was not regarded as a class effect, but rather as a drug-related risk. Further discussion during FDA review will probably rest on whether the increased efficacy benefit between the lower and higher doses justifies the increased safety risk. The manufacturer is seeking an indication for treatment of patients with moderate-to-severe RA.

The efficacy bar was higher for secondary endpoints, with an endpoint of ACR50, a 50% improvement in symptoms. Results were fairly similar between active treatment arms, with 33.8% of patients on the 5-mg dosage and 36.6% of those on the 10-mg dosage reaching that level of recovery compared with 12.7% of patients on placebo.

Efficacy endpoints at 6 months were: Clinical improvement (ACR20): 52.7% on the 5-mg dosage; 58.3% on the 10-mg dosage. Remission: 11% on the 5-mg dosage and 14.8% on the 10-mg dosage.

Efficacy endpoints at 3 months were: Change from baseline in HAQ-DI (Health Assessment Questionnaire Disability Index): 0.46 decline in disability on the 5-mg dosage; 0.56 decline in disability on the 10-mg dosage.

In this 12-month study, patients with RA who were treated with background, nonbiologic, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate were randomized to one of the tofacitinib arms for the next 6 months. At 3 months, nonresponding patients on placebo were reassigned to one of the tofacitinib arms. At 6 months, the remaining patients on placebo were put on one of the two dosages of tofacitinib.

Proximal signaling pathways upon stimulation of immune receptors in T cells

Once all patients were put on tofacitinib, the placebo patients achieved treatment responses similar to other tofacitinib patients, and all were able to maintain improvements through 12 months.

Kremer J, Li Z-G, Hall S, et al. Tofacitinib (CP-690,550), an oral JAK inhibitor, in combination with traditional DMARDS: phase 3 study in patients with active rheumatoid arthritis with inadequate response to DMARDS.

Baricitinib (Lilly and Company/Incyte) Inhibits JAK1 and JAK2: Phase IIb Data

A second oral JAK inhibitor for RA is not far behind tofacitinib. Researchers announced promising results for baricitinib from a phase IIb study at the European League Against Rheumatism (EULAR) Congress in June 2012, only a month after tofacitinib was moved forward by the FDA Advisory Committee. Trial results showed significant efficacy in patients with active RA. Baricitinab was administered in a combination regimen with methotrexate.

A placebo-controlled, dose-ranging study showed statistically significant differences in achieving the ACR20 score between placebo (41%) and the two highest-dose baricitinib groups (76%) at 12 weeks. A significant difference was also observed at the earliest assessment point, after 2 weeks of treatment, and was sustained to 12 weeks.

This was a small study of 301 patients with active RA who were on stable doses of methotrexate. Patients were randomized to receive placebo or one of four once-daily doses of baricitinib (1 mg, 2 mg, 4 mg, or 8 mg). Baricitinib is also being tested in phase II trials in patients with psoriasis.

Keystone E, Taylor P, Genovese M, et al. 12-week results of a phase 2B dose-ranging study of LY3009103 (INCB028050), an oral JAK1/JAK2 inhibitor, in combination with traditional DMARDs in patients with rheumatoid arthritis.

The Janus kinase ( JAK) molecule is an
immunomodulating signal transduction
agent, which has emerged as a new target
for rheumatoid arthritis (RA) research.

New Oral JAK Inhibitors Wait in the Wings

uring the past decade, changes in the treatment of rheumatoid arthritis (RA) have been accumulating faster than treatment experience can be evaluated. Consequently, the 2012 guideline revisions from the American College of Rheumatology (ACR) follow just four years after the previous version in 2008. The update is welcomed by clinicians, who must manage patients taking a range of different agents, choose treatment regimens based on tolerability and efficacy in each individual patient, and fit treatments to particular points in the progression of the disease.

Most of the changes in the 2012 revision reflect treatment lessons learned as biologic response modifier therapies have become better known (Table 1). A total of eight biologic agents were reviewed for the 2012 revision. In 2008, only five biologics were available for review: two nontumor necrosis factor (non-TNF) drugs, abatacept (a selective co-stimulation modulator) and rituximab (a B-cell inhibitor), as well as three anti-TNF drugs, adalimumab, etanercept, and infliximab.

The 2012 guidelines added another non- TNF biologic, tocilizumab (which blocks the IL-6 messenger cytokine), and two additional anti-TNFs, certolizumab pegol and golimumab. The particular nomenclature separating these biologicsanti-TNFs and non-TNFs&mdash;is that used by the ACR, but both mechanisms of action are effective in halting RA disease progression. Clinicians are able to select one or another of the drugs based on tolerability and effectiveness in individual patients.

Table 1. Biologic Agents Included in ACR Guidelines for RA

Tumor necrosis factor is a proinflammatory cytokine produced by the immune system. Excess levels of TNF are associated with inflammatory diseases such as rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. The anti- TNFs reduce TNF to control inflammation. Non- TNFs use other mechanisms to interrupt the inflammatory autoimmune response. Because both anti-TNF and non-TNF agents affect the immune response, they raise the risk of infection for patients taking them.

The anti-TNFs are the most familiar of the biologics, and the class has been used for more than 10 years to treat inflammatory conditions. Given by injection or infusion, these drugs are able to stop disease progression. Often, anti-TNFs as well as non-TNFs are used in combination with earlier disease-modifying antirheumatic drugs (DMARDs) to increase their potency, most often with methotrexate.

The 2012 guidelines focus on use of both DMARDs and biologics, making recommendations regarding selection of and switches between these agents. New recommendations favor early initiation of treatment (within the first 6 months following diagnosis) using triple-combination DMARD regimens

a biologic, with or without methotrexate, for patients who show high disease activity with poor prognosis. Biologics are not recommended for early RA in patients with lowto- moderate-disease activity and without poor prognosis.

Use of biologics as first-line therapy (in some patients) and beginning such treatment in early RA constitute two changes from the 2008 guidelines and probably better reflect existing practice patterns that changed as biologics became better understood.

An important addition in the 2012 revision is an update focused on safety issues that have become more apparent over time. The ACR makes new recommendations for use of biologic agents in high-risk patients, including patients who have hepatitis, congestive heart failure, or a history of malignancy, and are thus considered most at risk for infection. Table 2 shows recommended biologic agents for treatment of patients at risk.

In addition, screening for tuberculosis is recommended for all patients who are beginning or currently receiving biologic agents. Vaccinations are recommended for all patients taking DMARDs or biologic agents: pneumococcal, influenza, hepatitis B, human papillomavirus (HPV), and herpes zoster.

Table 2. ACR Recommendations for Use of Biologics in Patients With Hepatitis, Malignancy, or Congestive Heart Failure

In April 2012, the ACR released updated osteoarthritis (OA) guidelines. These were published in the April issue of

and are on the website (www. rheumatology.org) for easy downloading. The OA guidelines address pharmaceutical as well as nonpharmaceutical treatments for the hand, hip, and knee.

In June 2012, the ACR released updated guidelines for treatment of lupus nephritis. These guidelines were published in the June issue of

The ACR maintains the ACR Rheumatology Clinical Registry. The registry is a free, easyto- use, Web-based tool developed to assist members in practice. It is also available as an application for handheld devices. The registry delivers information based on local population management; it is integrated with national qualitycare programs and contains quality measures aimed at improving care and drug safety for patients with rheumatoid arthritis, osteoarthritis, osteoporosis, gout, and juvenile idiopathic arthritis.

In 2011, the registry enabled electronic submission and retrieval capabilities to support exchange of information with the Centers for Medicare & Medicaid Services (CMS) Physician Quality Reporting System (PQRS) and the Electronic Prescribing Incentive Program (eRx). More details about the registry are available on the ACR website.

Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis.

American College of Rheumatology website. Available at http://www.rheumatology.org. Accessed June 21, 2012.

During the past decade, changes in the
treatment of rheumatoid arthritis
(RA) have been accumulating faster
than treatment experience can be evaluated.

2012 Treatment Guidelines for Rheumatoid Arthritis: An Update from the American College of Rheumatology

espite decades of investigation, the causes of rheumatoid arthritis (RA) have remained elusive. In fact, research has indicated that there is unlikely to be a single root cause. Different paths of investigation have provided sometimes contradictory lines of evidence leading to multiple biologic triggers setting off the autoimmune response that causes RA.

Recently, animal studies have produced findings that argue for a broader causal theory that supports a targeted &ldquo;cure.&rdquo; Researchers who developed a mouse model for RA found that it took multiple regulatory T cells, rather than any specific one, to prevent the immune system from generating the tissue-specific inflammation that is the hallmark of RA. The cumulative effect of an array of diverse T cells introduced into the mouse was more effective in mediating the RA response than the single T cell that investigators expected to activate the receptor and trigger an inflammatory response. It was the diversity of the array that protected against RA. If the diversity is not present, the researchers reported, the immune system attacks the joints.

&ldquo;Our results, surprisingly, show that suppressing the immune response against a single target will not shut down the inflammatory response that causes rheumatoid arthritis.&rdquo;

The Wistar Institute announced the results of this research in the May 2012 issue of

. Andrew Caton, PhD, the senior author, said, &ldquo;Our results, surprisingly, show that suppressing the immune response against a single target will not shut down the inflammatory response that causes rheumatoid arthritis. Instead, an array of inflammation-stimulating antigens may be involved in causing the disease.&rdquo; An array of regulatory T cells is required to temper it.

The mouse model investigations also pointed to a possible reason that RA affects membranes that line the joints. Regulating T cells also influenced receptor T cells to produce interleukin-17 (IL-17), which travels through the body&rsquo;s lymphatic system. The lymphatic system drains into the joints. Caton suggests that, &ldquo;&hellip;the joint inflammation is a side effect of the natural tendency of these cells [IL-17] to accumulate in these areas of the body.&rdquo;

The Wistar Institute. Regulatory immune cell diversity tempers autoimmunity in rheumatoid arthritis [press release]. Philadephia, PA:

; May 8, 2012. Available at: http:// www.sciencedaily.com/releases/2012/05/120508142626.htm. Accessed May 21, 2012.

Oh S, Aitken M, Simons DM, et al. Requirement for diverse TCR specificities determines regulatory T cell activity in a mouse model of autoimmune arthritis [published online ahead of print March 26, 2012].

Despite decades of investigation, the
causes of rheumatoid arthritis (RA) have
remained elusive.

Arthritis | Targeted Therapies

News From EULAR 2012: New Drug Targets Emerge for RA

New Oral JAK Inhibitors Wait in the Wings

2012 Treatment Guidelines for Rheumatoid Arthritis: An Update from the American College of Rheumatology

Researching the Cause of Rheumatoid Arthritis