Arthritis Information http://www.hopkinsarthritis.org Johns Hopkins Arthritis Center Wed, 17 Dec 2014 16:34:37 +0000 en-US hourly 1 http://wordpress.org/?v=4.1 Apremilast (Otezla) approved by FDA http://www.hopkinsarthritis.org/arthritis-news/psoriatic-news/apremilast-otezla-approved-by-fda/ http://www.hopkinsarthritis.org/arthritis-news/psoriatic-news/apremilast-otezla-approved-by-fda/#respond Mon, 28 Apr 2014 16:41:34 +0000 http://www.hopkinsarthritis.org/?p=20320 Apremilast (Otezla®) received FDA approval on March 21, 2014 for the treatment of adults with active psoriatic arthritis (PsA).  It is the first oral medication in the U.S. with an approved indication for the treatment of PsA. The recommended dose is 30 mg BID.

Apremilast is a phosphodiesterase 4 (PDE4) inhibitor which results in increased intracellular cAMP which helps to modulate the balance between pro-inflammatory and anti-inflammatory mediators produced by immune cells.

Pooled data from three multicenter, randomized controlled trials were analyzed to assess the efficacy and safety of apremilast.  A total of 1493 adults with active PsA (≥ 3 tender joints, ≥ 3 swollen joints) fulfilling CASPAR criteria were randomized (1:1:1) to either apremilast (20 mg BID or 30 mg BID) or placebo.  In one of the studies, patients were required to have at least 1 active psoriatic lesion measuring ≥ 2 cm.  Co-treatment with stable doses of DMARDs (methotrexate ≤ 25 mg weekly, leflunomide ≤ 20 mg daily, or sulfasalazine ≤ 2000 mg daily), corticosteroids (prednisone ≤ 10 mg daily equivalent), and NSAIDs were permitted. However, co-treatment with a TNF inhibitor was not permitted.  Previous TNF inhibitor use was allowed, but patients with inadequate response to > 1 TNF inhibitor or > 3 DMARDs were excluded.  The primary study endpoint was ACR20 response at Week 16.  A significantly higher proportion of patients in the apremilast 30 mg BID group achieved an ACR20 response compared to placebo (32-41% vs. 18-19%, respectively, p<0.05).  In one of the RCTs, active plaque psoriasis improved significantly among those who received apremilast 30 mg BID compared to placebo (PASI75: 21% vs. 5%, respectively).  Enthesitis and dactylitis were improved in subjects receiving the higher dose of apremilast.  Physical functioning at Week 16 as measured by HAQ-DI improved in apremilast 30 mg BID compared to placebo (-0.24 vs. -0.09, respectively).

Notable adverse events with apremilast include diarrhea/nausea, depression, weight loss, and drug-drug interactions. To limit the GI side effects which occur especially during medication initiation, a dose escalation schedule during the first 5 days of use is advised. Due to a higher proportion of patients who reported depression with apremilast compared to placebo (1.0% vs. 0.8%, respectively), patients should be assessed for depression and suicidal ideation before and during continued use. Weight loss may also occur with apremilast (5-10% of body weight in 10% of patients receiving apremilast 30 mg BID compared to 3.3% with placebo). Because apremilast is metabolized via the cytochrome P450 pathway, inducers of cytochrome P450 (e.g. phenytoin, carbamazepine, rifampin, etc.) are not recommended to be co-administered with apremilast.

For patients with significant renal insufficiency (CKD stage 4 or higher, eGFR < 30 mL/min), the dose of apremilast should be reduced to 30 mg daily.

Apremilast is a pregnancy class C medication, with limited safety data in pregnant women. A registry has been established to follow outcomes of apremilast in this patient population. The safety of apremilast use during lactation is similarly limited.

Editorial

PsA is chronic inflammatory arthritis in the presence of skin and/or nail psoriasis. Though it is classified as a single disease entity, PsA has at least 5 clinical phenotypes as first described by Moll and Wright. Depending on the subtype and severity of disease, various medications can be used either singly or in combination to control the symptoms and signs of PsA.

Current management of adults with active PsA includes NSAIDs, corticosteroids, DMARDs such as methotrexate, leflunomide, and sulfasalazine, as well as biological agents (e.g. TNF inhibitors and an anti-IL12/23 inhibitor). For patients with milder disease, a single DMARD may suffice, whereas those with more severe disease will likely require co-treatment with a DMARD and biologic.  Despite the availability of an increasing number of medications to treat PsA, some patients may not achieve an adequate clinical response. Consequently, there appears to be an unmet need for additional medications in the rheumatologist’s armamentarium in the treatment of PsA.

The recent FDA approval of apremilast in the treatment of adults with active PsA is welcome news for rheumatologists and other healthcare providers who care for these patients.  To some extent, it marks a monumental moment in the annals of PsA management since apremilast is the first oral medication with an approved indication for the treatment of PsA.  Despite the widespread use of methotrexate in the U.S. for PsA, methotrexate, along with leflunomide and sulfasalazine, are used off-label.  And many patients who use these medications may still have inadequate clinical response. Based on pooled data from 3 separate RCTs consisting of nearly 1500 patients with active PsA, the efficacy of apremilast at 30 mg BID was deemed by the federal regulators at FDA to outweigh the risks of medication.

Compared to the efficacy of TNF inhibitors as a class in PsA, apremilast appears to be slightly less effective.  TNF inhibitors in RCTs have been reported to have an ACR20 response of 50-60% at Week 24 compared to apremilast’s ACR20 response of 45% at Week 24.  Since the RCTs with apremilast allowed for enrollment of TNF inhibitor-inadequate responders, it is conceivable that the lower treatment response can be attributed in part to the more refractory disease in this specific subpopulation of patients with PsA.  Notably, the response to skin psoriasis is markedly less effective in apremilast compared to most TNF inhibitors (PASI 75: 21% vs. 56-60%, respectively).  The side effect profile of apremilast is reassuring with respect to major infections, including tuberculosis and invasive fungal infections, observed occasionally with TNF inhibitors.  There were no reports of these types of infections among patients receiving apremilast.  Typical infections with apremilast appear to be mild, with mostly URIs and nasopharyngitis reported in 3.9% and 2.6% of patients, respectively.  Nonetheless, GI side effects including diarrhea and nausea were significantly reported with apremilast—especially during drug initiation, prompting a dose titration during the first 5 days of use to the target dose of 30 mg BID.  Depression was reported to be higher among patients receiving apremilast compared to placebo.  However, among small molecules in the family of PDE4 inhibitors, apremilast has a higher therapeutic index and can be used more safely in patients with PsA.  Weight loss of up to 5-10% body weight occurred in 10% of patients receiving apremilast 30 mg BID.  Whether this is related to the GI side effects associated with apremilast use is unclear.

Given the relatively safer side effect profile but the lower effectiveness of apremilast compared to TNF inhibitors, where does apremilast fit into the treatment algorithm in PsA?  In patients with mild-to-moderate disease activity who have inadequate response to methotrexate, but with mild psoriasis, the addition of apremilast may make more sense than adding a TNF inhibitor.  Similarly, for PsA patients who are well-controlled on a biological agent but who experience frequent severe infections, then treatment with apremilast instead may be clinically indicated.

Before apremilast can be more broadly adopted in the management of PsA, several questions need to be clarified.  Given the heterogeneity of PsA clinical phenotypes, does apremilast work equally well in the spondyloarthritis subtype as it does the symmetric polyarthritis subtype?  There is some level of uncertainty as to the disease-modifying effectiveness of methotrexate in preventing radiographic progression in PsA.  Is apremilast like methotrexate, or does it work as well as TNF inhibitors in preserving joint integrity and physical functioning after many years of continued use?  What about patients with severe dactylitis and enthesitis?  Given the preliminary data from the RCTs, apremilast does not appear to be as effective as TNF inhibitors in treating these conditions.  Is that more related to its duration of therapy rather than its mechanism of action? Finally, the unanswered questions of depression and weight loss warrant further investigation.

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Current Saline Shortage http://www.hopkinsarthritis.org/arthritis-news/current-saline-shortage/ http://www.hopkinsarthritis.org/arthritis-news/current-saline-shortage/#respond Sat, 12 Apr 2014 12:49:18 +0000 http://www.hopkinsarthritis.org/?p=20298 The current nationwide saline shortage has the potential to negatively impact rheumatology patients dependent on infusible products to manage their disease.  Bags of normal saline (0.9%) in the 250ml-1000ml volumes are especially low.  An announcement by the FDA on March 24, 2014 also states 0.45% (1/2 NS) saline bags in volumes of 500ml and 1000ml are also in decreased supply.  The FDA foresees this shortage to remain a problem at least into May 2014.  Hospitals have begun rationing saline and looking to alternatives for fluid replacement.  Rationing is not an alternative in infusion centers that are not hospital based.

The American Society of Health-System Pharmacists has published Intravenous Solution Conservation Strategies.  This document can be found at:  http://www.ashp.org/DocLibrary/Policy/Conservation-Strategies-for-IV-Fluids.pdf_

Not all fluids are compatible with biologic infusibles.   Before substituting an alternative to 0.9% normal saline, please contact the pharmaceutical company to find out if a safe alternative can be used.   For example, Janssen has clinical trial data on 0.45% normal saline and infliximab.  Click here for publication.

The table below defines the solutions used with infusible medications for rheumatic diseases.  This information has been compiled from the prescribing information for each medication. Also listed are the medical information numbers for each manufacturer.

Tocilizumab Actemra 0.9% Sodium Chloride Genentech 800 821-8590
Belimumab Benlysta 0.9% Sodium Chloride GlaxoSmithKline 877-356-8368
Cyclophosphamide Cytoxan 5% dextrose
5% dextrose and 0.9% sodium chlorideLactated Ringer’s0.45% sterile sodium chloride
Bristol Myers Squibb 800-321-1335
IVIg 5% Dextrose0.9% Sodium Chloride CSL BehringBaxter 800-504-5434  (Privigen)866-424-6724 (Gammagard)
Abatacept Orencia 0.9% Sodium Chloride Bristol Myers Squibb 800-321-1335
Infliximab Remicade 0.9% Sodium Chloride Janssen 800-526-7736
Rituximab Rituxan 0.9% Sodium Chloride5% Dextrose in Water Genentech 800 821-8590
Golimummab Simponi Aria 0.9% Sodium Chloride Janssen 800-526-7736
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Patients Increase Public Awareness of Underestimated Disease http://www.hopkinsarthritis.org/arthritis-news/patients-increase-public-awareness-of-underestimated-disease/ http://www.hopkinsarthritis.org/arthritis-news/patients-increase-public-awareness-of-underestimated-disease/#respond Sat, 01 Feb 2014 15:36:07 +0000 http://www.hopkinsarthritis.org/?p=20192 January 22, 2013 – Rheumatoid Patient Foundation (RPF) announces the establishment of Rheumatoid Awareness Day to be held each year on February 2, giving people with the chronic illness known as rheumatoid arthritis, or rheumatoid disease, a day of recognition. Because the disease is commonly presumed to be a type of arthritis, awareness is lacking, causing problems with disability accommodations, clinical care, healthcare reimbursement and research funding.

February 2 already boasts the observance of Groundhog Day, from which several analogies can be drawn to rheumatoid disease. “Compare disease onset to the moment the groundhog comes out of his hole to look for his shadow,” says Kelly Young, founder of the RPF. “It’s impossible to predict how aggressive the disease will be or whether treatments will be effective. The six weeks that the groundhog forecasts correspond to the short window of opportunity for people with rheumatoid disease to get early diagnosis and treatment, which has been shown to be a crucial component of positive outcome.”

The Rheumatoid Patient Foundation will support the first annual Rheumatoid Awareness Day with a campaign aimed at raising awareness and educating about rheumatoid disease. RPF encourages both the rheumatoid patient community and the public to get involved by sharing educational resources, promoting awareness messages via social media, participating in a live online chat and a matching donation opportunity. For information on how to support Rheumatoid Awareness Day, visit http://rheum4us.org/rheumatoid-arthritis-awareness-day/.
Rheumatoid Patient Foundation

RPF is a 501c(3) non-profit organization dedicated to improving the lives of people with rheumatoid diseases such as rheumatoid arthritis and juvenile arthritis. RPF was founded in 2011 to address significant lack of disease education, comparatively low levels of research funding, and difficulty obtaining adequate treatment. RPF is committed to creating pathways to better clinical care and disease outcomes through education, awareness, and participation in patient-centered research. For more information, visit http://rheum4us.org.

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Certolizumab pegol gains FDA approval for PsA and AS http://www.hopkinsarthritis.org/arthritis-news/certolizumab-pegol-fda-approval-psoriatic-arthritis-ankylosing-spondylitis/ http://www.hopkinsarthritis.org/arthritis-news/certolizumab-pegol-fda-approval-psoriatic-arthritis-ankylosing-spondylitis/#respond Thu, 24 Oct 2013 16:00:24 +0000 http://www.hopkinsarthritis.org/?p=20035 Certolizumab pegol (Cimzia®) gained FDA approval in September/October 2013 for two new indications, adults with active psoriatic arthritis (PsA) and adults with active ankylosing spondylitis (AS). Already approved for adults with Crohn’s Disease and Rheumatoid Arthritis, certolizumab pegol (CZP) is a humanized TNF-α monoclonal antibody.

In the RAPID-PsA study, a 24-week, phase 3 double-blind, randomized, placebo-controlled trial of adults with active PsA (≥3 tender joints, ≥3 swollen joints, C-RP > 7.9 mg/L or ESR ≥ 28 mm/hr) for ≥ 6 months and fulfilling the CASPAR criteria with previous failure of ≥ 1 DMARD) and active or documented history of plaque psoriasis, subjects (N=409) were randomized (1:1:1) to receive placebo or CZP 400 mg at weeks 0, 2, and 4 followed by either CZP 200 mg every 2 weeks or CZP 400 mg every 4 weeks thereafter. The primary study endpoint was ACR20 response at week 12. A significantly higher proportion of patients in both active treatment groups achieved an ACR20 response at week 12 compared to placebo (52% in the CZP 200 mg Q2 weeks, 58% in the CZP 400 mg Q4 weeks, 24% in placebo, p<0.001). Efficacy was maintained through week 24. Subjects assigned to placebo who failed to attain a pre-specified 10% improvement in the total number of tender and swollen joints at week 16 underwent early escape and were re-randomized to receive CZP 200 mg Q2 weeks or CZP 400 mg Q4 weeks. Active plaque psoriasis improved significantly among those who received CZP, with 46% among the 200 mg Q2 weeks group and 47% among the 400 mg Q4 weeks group achieving a PASI75 at week 12 compared to 14% among placebo (p<0.001). Efficacy for both the ACR20 response and PASI75 was maintained through 24 weeks. Concomitant DMARD use, most frequently methotrexate, did not appear to impact response to CZP.  Dactylitis and enthesitis were both significantly improved in subjects receiving CZP as compared to placebo. Risk of adverse events, including upper respiratory tract infection and diarrhea, was similar between all groups through 24 weeks. There were 2 deaths in the CZP groups (1 myocardial infarction, 1 unknown cause) during the study, both considered by the investigators to be unrelated to study drug.

In the RAPID-axSpA study, a 24-week, phase 3 double-blind, randomized, placebo-controlled trial of adults with axial spondyloarthritis (axSpA) including ankylosing spondylitis (AS). All participants had chronic inflammatory back pain for ≥ 3 months, fulfilling the ASAS criteria for axSpA, with active disease defined by BASDAI ≥ 4 and spinal pain ≥ 4 on the 0-10 Numerical Rating Scale, along with C-RP > 7.9 mg/L and/or sacroiliitis on MRI. Eligible participants must have had inadequate response to at least 1 NSAID for ≥ 30 days or 2 NSAIDs for ≥ 2 weeks each. A pre-specified number (≤ 40%) of patients could have received treatment with an anti-TNF agent > 3 months prior to baseline. To ensure a balanced study population of patients, approximately 50% of axSpA patients fulfilled mNY criteria for AS. Subjects (N=325) were randomized (1:1:1) to receive to placebo or CZP 400 mg at weeks 0, 2, and 4 followed by CZP 200 mg Q2 weeks or CZP Q4 weeks thereafter. The primary study endpoint was ASAS20 at week 12. A significantly higher proportion of patients in both active treatment groups achieved an ASAS20 response at week 12 compared to placebo (57% in the CZP 200 mg Q2 weeks, 63% in the CZP 400 mg Q4 weeks, 38% in placebo, p=0.004 and p<0.001, respectively). Efficacy was maintained through 24 weeks. Secondary endpoints, including BASFI and BASMI for physical functioning and spinal mobility, respectively, were significantly improved among active treatment groups compared to placebo. ASDAS, a disease activity measure for axSpA, was also significantly improved among the active treatment arms compared to placebo at weeks 12 and 24. In subgroup analyses, treatment effect of CZP was similar among patients with AS and non-radiographic axSpA. Risk of adverse events, including nasopharyngitis and upper respiratory tract infection, was similar between all groups through 24 weeks. There was an increased risk of elevated CPK in the CZP groups compared to placebo (5.1% vs. 1.9%, respectively). The CPK elevation, which was transient and promptly resolved, was considered by the investigators to be associated with increased physical exercise. There were no reported deaths in the study.

References:

  • Mease PJ, Fleischmann R, Deodhar AA, et al. Ann Rheum Dis 2013 Oct 16. [Epub ahead of print].
  • Landewe R, Braun J, Deodhar A, et al. Ann Rheum Dis 2013 Sept 6. [Epub ahead of print].

***The information above will be amended as necessary, pending presentation of additional, pertinent study data at the 2013 ACR Annual Scientific Meeting in San Diego, CA from October 27-30, 2013.

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OTREXUP™ (methotrexate) injection approved by the FDA http://www.hopkinsarthritis.org/arthritis-news/otrexup-methotrexate-injection-approved-by-the-fda/ http://www.hopkinsarthritis.org/arthritis-news/otrexup-methotrexate-injection-approved-by-the-fda/#respond Mon, 21 Oct 2013 16:00:15 +0000 http://www.hopkinsarthritis.org/?p=20028 OTREXUP™ (methotrexate) injection was recently approved by the U.S. Food and Drug Administration.

It is indicated for adults with severe, active rheumatoid arthritis, or children with active polyarticular juvenile idiopathic arthritis who have failed first line therapies.  It is also indicated for severe, recalcitrant, disabling psoriasis.

OTREXUP™ is delivered by auto injector as a subcutaneous injection.  It will be available in four dose strengths: 10mg, 15mg, 20mg, and 25mg.

Side effects of Otrexup are unchanged for other formulations of methotrexate.

Patients using any form of methotrexate must be counseled on risks of toxicity, proper administration, risks of pregnancy and nursing, and proper storage and disposal, and the need for frequent, ongoing monitoring.

Editorial Note:  While patients are very receptive to administration of medication by auto-injector, price and insurance coverage may be the determining factor in switching from oral methotrexate to Otrexup vs. vial and syringe.

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Ustekinumab (Stelara®) receives FDA approval for treatment of adults with active psoriatic arthritis http://www.hopkinsarthritis.org/arthritis-news/ustekinumab-stelara-fda-approval/ http://www.hopkinsarthritis.org/arthritis-news/ustekinumab-stelara-fda-approval/#respond Mon, 07 Oct 2013 16:00:14 +0000 http://www.hopkinsarthritis.org/?p=20030 Ustekinumab (Stelara®) received FDA approval in September 2013 for a new indication of the treatment of adults with active psoriatic arthritis (PsA), alone or in combination with methotrexate. Already indicated for the treatment of adults with moderate-to-severe plaque psoriasis, ustekinumab is a human IgG1κ monoclonal antibody against the p40 subunit of IL12/23. In the pivotal PSUMMIT 1 trial, a phase 3, multicenter, randomized controlled trial of adults with active PsA (≥ 5 tender joints, ≥ 5 swollen joints, C-RP ≥ 3.0 m/L, and active or documented history of plaque psoriasis) fulfilling CASPAR criteria, subjects (N=615) were randomized (1:1:1) to receive ustekinumab 45 mg, ustekinumab 90 mg, or placebo subcutaneously at weeks 0, 4, and then every 12 weeks thereafter. The primary study endpoint was ACR20 response at week 24. A significantly higher proportion of patients in both active treatment groups achieved an ACR20 response compared to placebo (42% in the ustekinumab 45 mg group, 50% in the ustekinumab 90 mg group, and 23% in placebo, p<0.0001). Efficacy was maintained through week 52. Subjects assigned to placebo and who then crossed over to active drug (ustekinumab 45 mg or 90 mg) at week 16 were able to attain a similar ACR20 response at week 52 compared to those who received active drug throughout. Active plaque psoriasis improved significantly among those who received ustekinumab, with 57% among the 45 mg group and 62% among the 90 mg group achieving a PASI75 compared to 11% among placebo (p<0.0001). Dactylitis and enthesitis were both significantly improved in subjects receiving ustekinumab as compared to placebo. Risk of adverse events, including nasopharyngitis, upper respiratory tract infection, headache, and fatigue, was similar for all groups. Before starting treatment with ustekinumab for PsA, patients should be screened for TB. The recommended dose is 45 mg subcutaneously at weeks 0, 4, and then every 12 weeks thereafter. For those with co-existing moderate-to-severe plaque psoriasis weighing > 100 kg, the recommended dose is 90 mg at the aforementioned time intervals.

References:

  • McInnes IB, Kavanaugh A, Gottlieb AB, et al. Lancet 2013;382:780-9.
  • Ustekinumab Package Insert (www.stelarainfo.com/pdf/PrescribingInformation.pdf)
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Tofacitinib: A novel Janus kinase inhibitor is FDA approved as the first oral biologic treatment for rheumatoid arthritis http://www.hopkinsarthritis.org/arthritis-news/tofacitinib-fda-approved-oral-biologic-for-rheumatoid-arthritis/ http://www.hopkinsarthritis.org/arthritis-news/tofacitinib-fda-approved-oral-biologic-for-rheumatoid-arthritis/#respond Thu, 10 Jan 2013 16:02:05 +0000 http://www.hopkinsarthritis.org/?p=19541 Tofacitinib (Xeljanz®) is the first of a unique class of oral kinase inhibitors to be FDA approved for the treatment of rheumatoid arthritis (RA). Tofacitinib is a selective inhibitor of Janus kinase (JAK) enzymes. JAKs mediate signaling by surface receptors for several important cytokines that are fundamental to the propagation of inflammation in RA. JAK enzymes (JAK1, JAK3) are responsible for activating Signal Transducers and Activators of Transcription (STATs) which further modulate intracellular activity and gene expression. Tofacitinib prevents signaling of JAK enzymes and therefore interrupts important signal transduction of cytokines which contribute to the aberrant immune response in RA.

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:

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. 

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.

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Staying Healthy with Arthritis: Body AND Mind http://www.hopkinsarthritis.org/arthritis-news/staying-healthy-with-arthritis-body-and-mind/ http://www.hopkinsarthritis.org/arthritis-news/staying-healthy-with-arthritis-body-and-mind/#respond Wed, 15 Aug 2012 17:00:50 +0000 http://www.hopkinsarthritis.org/?p=19106 Depression and anxiety are more common among individuals with arthritis than among the general population. Yet, these mood disorders are still underdiagnosed and undertreated in arthritis patients despite data that depression and anxiety affect important outcomes such as functional ability, pain, and quality of life. The following study sought to characterize the burden of anxiety and depression among adults in the United States with arthritis over the age of 45 years and to identify factors associated with anxiety and depression in this population [Murphy LB, et al. Anxiety and depression among US adults with arthritis: prevalence and correlates. Arthritis Care & Research 2012;64(7):968-976].

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.

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Challenges in Screening for Latent TB in Inflammatory Arthritis http://www.hopkinsarthritis.org/arthritis-news/ra-news/challenges-in-screening-for-latent-tb-in-inflammatory-arthritis/ http://www.hopkinsarthritis.org/arthritis-news/ra-news/challenges-in-screening-for-latent-tb-in-inflammatory-arthritis/#respond Mon, 30 Jul 2012 17:00:00 +0000 http://www.hopkinsarthritis.org/?p=19103 TNFα inhibitors have demonstrated great efficacy for the treatment of rheumatoid arthritis (RA). However, they are not without potential side effects with one being the reactivation of latent tuberculosis (TB). This complication can be minimized by screening for latent TB prior to the initiation of a TNFα inhibitor and initiating treatment. Unfortunately, there is no gold standard by which to screen for latent TB. Tuberculin skin testing with purified protein derivative (PPD) is commonly used as a screen for TB before the initiation of TNFα inhibitors; although imperfections in the test (particularly for individuals already on immunosuppression) are not insignificant. The following study summarized below sought to compare the standard PPD test to the interferon-gamma release assay (IGRA) blood test for latent TB screening among patients with RA, psoriatic arthritis, or ankylosing spondylitis starting the TNFα inhibitor, golimumab [Hsia EC, et al. Interferon-gamma release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Arthritis & Rheumatism 2012;64(7):2068-2077].

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.

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Pregnancy Concerns Among Women with Rheumatoid Arthirits and Lupus http://www.hopkinsarthritis.org/arthritis-news/pregnancy-concerns-among-women-with-rheumatoid-arthirits-and-lupus/ http://www.hopkinsarthritis.org/arthritis-news/pregnancy-concerns-among-women-with-rheumatoid-arthirits-and-lupus/#respond Sun, 15 Jul 2012 17:00:13 +0000 http://www.hopkinsarthritis.org/?p=19112 Many autoimmune diseases have a female predominance. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are no exception. Both of these diseases can affect young women in their reproductive years, but little is known about the impact of RA and SLE on a woman’s opinion regarding pregnancy or, further, how this translates into family planning. This study [Clowse ME, et al. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care & Research 2012; 64(5):668-74] sought to determine if women with RA or SLE had fewer children than those diagnosed later in life, and if so, the reasons and causes behind such differences.

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

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