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PROCEEDINGS

Proceedings of the 2012Rheumatology Winter Clinical Symposia

Arthur Kavanaugh, MD,* George Martin, MD,† John J. Cush, MD,‡

Martin J. Bergman, MD,§ Roy Fleischmann, MD,�

Orrin M. Troum, MD,¶ Vibeke Strand, MD,**Eric M. Ruderman, MD,†† and Alvin F. Wells, MD, PhD‡‡

Recent years have witnessed important developments in rheumatology. Novel diagnostic methods,stratification approaches, and treatment paradigms have been brought into the clinic for a numberof rheumatologic and autoimmune diseases. In addition, there have been developments in relatedmedical disciplines that are relevant to the care of patients with rheumatic diseases. Keeping pacewith these many developments is a challenge, and clinical rheumatologists have used variousmethods to educate themselves about these advances. In January 2012, the 5th annual Rheuma-tology Winter Clinical Symposium was held. At this meeting, faculty and participants helddiscussions and exchanged knowledge about new scientific data and how it may impact the care ofrheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clin-ical Symposium 2012 are included in this review. These and other presentations can be viewed intheir entirety at http://www.r-w-c-s.com.© 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:923-926

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EXTRA-ARTICULARUSE OF MUSCULOSKELETALULTRASOUND IN RHEUMATOLOGY

Increasing numbers of rheumatologists in NorthAmerica have begun to evaluate whether the use ofmusculoskeletal ultrasound will enhance the overall

are of their patients. To date, this has been focusedainly on the diagnosis of patients with inflammatory

rthritis such as rheumatoid arthritis (RA) as well as mon-toring the response to therapy. Similar to magnetic reso-ance imaging and computed tomography scanning, ul-rasound is able to detect changes in the synovium,artilage, and bone but at a much lower cost and without

*UCSD Department of Medicine, La Jolla, CA.†Dermatology and Laser Center of Maui, Maui, Hawaii.‡Department of Medicine, Baylor Research University, Dallas, TX.§Department of Medicine, Drexel University college of Medicine, Philadelphia, PA.�Department of Medicine, University of Texas Southwestern Medical Center, Dallas,TX.¶USC Medical School, Los Angeles, CA.**Division of Immunology/Rheumatology, Standford University, Palo Alto, CA.††Department of Medicine, Northwestern University School of Medicine, Chicago,IL.‡‡Rosalind Franklin University of Medicine and Science, Chicago, IL.

uAddress reprint requests to John J. Cush, MD, Baylor Research Institute, 9900 N.

Central Expressway, Suite 550, Dallas, TX 75231. E-mail: jjcush@gmail.com.

0049-0172/12/$-see front matter © 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.semarthrit.2012.03.002

he use of radiation. In addition to detecting changes inhe synovium and bone, musculoskeletal ultrasound is areat clinical tool that may be used in the diagnosis andonitoring of other rheumatic conditions. Some of the

onditions include seronegative arthropathies (eg, psori-tic arthritis, enthesitis), crystalline arthritis (eg, gout,seudogout), polymyalgia rheumatica, temporal arteritis,cleroderma, Sjögren’s syndrome, and fibromyalgia.

Although the use of ultrasound in some of the aboveonditions is still in the early stages of clinical develop-ent, the use of more sensitive ultrasound transducers

nd a portable ultrasound machine will make these andther rheumatic conditions more readily assessable to theracticing rheumatologists and to other physicians treat-ng patients with musculoskeletal disorders.—A.F. Wells

PPROACH TO INFLAMMATORY MYOSITIS

diopathic inflammatory myositis is a rare disorder thatffects 2 to 7 persons per million each year. Although theistoric Bohan and Peter classification system remains

nstructive, new criteria and classifications have been fos-ered by the identification of well-characterized autoan-ibody subsets, including the antisynthetase antibodyyndrome. This overview also focuses on several un-

sual myopathic disorders, including orbital myositis,

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focal myositis, inclusion body myositis, myositis ossi-ficans, and necrotizing myositis related to statin thera-pies. Although statin-induced myopathic complaintsare quite common, it has been estimated that up to 6%of myositis patients may have statin-induced necrotiz-ing myositis that appears to be associated with an an-tibody against a 100-kDa autoantigen (3-hydroxy-3-methylglutaryl coenzyme reductase). Another novelentity is dermatomyositis sine myositis, also known as clini-cally amyopathic dermatomyositis. Such patients have a lowrisk (�10%) of developing systemic myositis and weaknessbut may be at risk for severe interstitial lung disease. Chroniclung disease, serious infections (25% to 35%), and oppor-tunistic infections (�10%) may complicate the manage-ment of idiopathic inflammatory myositis patients.—J. J.Cush, MD

ICD-10

Unless changed by the US Congress, in October 2013there will be a dramatic change in how physicians in theUS code for work done, specifically, in how the diagnosesare reported. At that time, the official coding system willswitch from the current ICD9-CM to ICD-10. Thechange has been a long time coming, being legislated aspart of the Health Insurance Portability and Accountabil-ity Act of 1996. The change will bring the USA in linewith most of Europe and parts of Canada.

The reasons for adopting these changes are multiple.The current ICD9-CM has limited numbers of codes(approximately 13,000), is often nonspecific, and reflectsthe state of the art as regards medical knowledge fromabout the 1970s. The new coding system, by being up to7 digits long, will allow for 68,000 codes, will be moreflexible and specific, and will allow for laterality. For ex-ample, M05.761 is the code for Seropositive RA involvingthe right knee (M05.7 � seropositive RA without otherorgan system involvement; plus 6 � knee; plus 1 � right)and MA1A.9820 would indicate chronic gout of left toewithout tophi (M1A.9 � chronic gout unspecified etiol-ogy; plus 8 � toe; plus 2 � left; plus 0 � no tophi).

Making the switch from ICD9 to ICD-10 will be cum-bersome, but not impossible. Office practices, superbills,computer software, and billing systems will need to beupdated. Staff will need to be trained, particularly thoseresponsible for coding and billing. It is estimated that theswitch will take up to 36 months to complete and may cost$2400–$46,000 to implement, depending on the size of thepractice. However, the implementation of ICD-10 will oc-cur, whether you are ready or not. The best time to startpreparing is now.—J. M. Bergman, MD

ADVANCES IN RHEUMATOIDARTHRITIS THERAPIES

2011 was an exciting year in the development of new

therapeutics for the treatment of RA. Phase 3 results were a

released on the efficacy and safety of tofacitinib in com-bination with DMARDs and methotrexate, and com-pared to adalimumab and in TNF inhibitor (TNFi)failures. Effects on radiographic inhibition were demon-strated. The safety profile has been better defined: thereappears to be less liver test elevation when used as mono-therapy and the lipid elevation can be corrected with theuse of lipid-lowering agents. Infections, including seriousand opportunistic, and herpes zoster have occurred. Thesafety of fostamatinib in phase 2 has been reported withincreased diarrhea and hypertension noted, but no lipidelevation. A report of a phase 2 study of another inhibitorof JAK3/1, VX09-509-101, showed efficacy as mono-therapy with perhaps a slightly different safety profilethan tofacitinib. The efficacy of tocilizumab as mono-therapy was presented; it is effective clinically and in in-hibiting radiographic progression, with less liver toxicitythan when used with concomitant methotrexate. Phase 2data were released on 2 new inhibitors of IL-6—theirefficacy and safety appear to be similar to tocilizumab.The recently approved subcutaneous formulation ofabatacept has equivalent safety and efficacy as the IV for-mulation. Screening for the JC virus, prior to rituximabtreatment, is not helpful in predicting the development ofPML. It was reported from a French registry that IgGlevels do decrease over repetitive courses of RTX and thismay be related to increased frequency of serious infec-tions; this is different from what has been shown in thecompany-sponsored long-term extensions.—R. Fleisch-mann, MD

OBESITY: INFLAMMATORY ASPECTSAND RELATED ISSUES IN RHEUMATOLOGY

Obesity now affects more than 30% of the US adult pop-ulation. The WHO reports that worldwide there are ap-proximately 1 billion adults who are overweight and 300million who are obese; of note, these numbers are ex-pected to rise. Increased body mass index is a major com-ponent of the metabolic syndrome (common in psoriasisand psoriatic arthritis) and is associated with an adversecardiovascular risk profile. Obesity is regarded as a sys-temic, low-grade inflammatory state, characterized by el-evated levels of C-reactive protein, TNF-�, IL-6, IL-1�,nd PAI-1. It is an unequivocal risk factor for the onsetnd progression of knee osteoarthritis. It increases cardio-ascular risk in RA and increases the risk of developingsoriatic arthritis, as reported at the 2011 American Col-

ege of Rheumatology national meeting.Adipose tissue is a dynamic endocrine organ that re-

eases cytokines and adipokines, including adiponectin,eptin, resistin, visfatin, and chemerin, promoting inflam-

ation and metabolic dysfunction. Additionally, obesityeads to increased infiltration of immune cells into meta-olic tissues, increased ratio of CD8� to CD4� T cells,nd decreased immunosuppressive T-regulatory cells, cre-

ting a favorable environment for immune activation.

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Therapeutic strategies in rheumatology should also ad-dress obesity as weight influences TNFi persistency inpsoriatic arthritis and also diminishes response to TNFi inRA patients.—Orrin M. Troum, MD

ETHICAL ISSUES IN CLINICALRESEARCH IN RHEUMATOLOGY

Clinical research is replete with ethical considerations.This is certainly true in rheumatology, as the introductionof highly effective biologic agents has raised a number ofethical questions concerning study design. For example,with these therapies available, what are the most appro-priate comparators for future studies of other new drugs?Under what circumstances, if any, should the use of pla-cebos be permitted? What is the responsibility of thesponsor or others to continue to provide expensive thera-pies to patients who have participated in clinical studies?One approach toward achieving greater insight intodifficult areas is to frame the discussion using several ofthe core principles of medical ethics: namely, patientautonomy, beneficence, nonmaleficence, and distribu-tive justice.

Many ethicists feel that patient autonomy may be thepreeminent ethical principle. The tangible expression ofpatient autonomy in clinical research is the process ofinformed consent. Key components of adequate informedconsent include decision-making capacity necessary tomake a meaningful choice, and the freedom to make adecision to participate without coercion or other influ-ence. Given the complexity of the scientific advances nowbeing tested in the clinic, it can be challenging to presentsuch information to patients in a way they can under-stand. In many countries, patients’ impetus to participatein a study may be driven by their lack of access to suchmedicines by other means—this can be viewed as a coer-cive influence.

The concept of beneficence is that clinicians will try toaccomplish benefit for their patients. Because clinical tri-als are big business, with billions of dollars at stake, it isimportant that investigators be free of conflict of interest,which could result in bias.

Nonmaleficence refers to the concept of keeping thepatient free from harm. A relevant consideration in clin-ical trials concerns the use of placebos in studies. Ques-tions on the ethical use of placebos (eg, duration) con-tinue to generate intense debate in rheumatology,especially as available therapies have improved.

Distributive justice has become an increasingly impor-tant consideration as clinical trials are done more broadlythroughout the world. If the standard of care for the treat-ment of patients with rheumatic diseases is different in agiven country, is it ethical to design a study based on thatstandard, even if such a study would not be consideredethical in another country with greater resources and ahigher standard of care? Consideration of ethical issues

will continue to be critical to the optimal assessment and b

use of novel therapeutic agents in rheumatology.—A.Kavanaugh, MD

ADVANCES IN SKINDISEASE MANAGEMENT 2012

This past year brought hope to patients suffering withstage IV melanoma with the approval of Ipilimumab (Ye-rvoy) in March 2011 and Vemurafenib (Zelboraf) in Au-gust 2011. Until now, no therapy has demonstrated dur-ing phase III controlled trials increased survival in patientswith stage IV disease. Ipilimumab, a human monoclonalantibody directed against CTLA-4, was found to increasethe median and 1- and 2-year survival rates in stage IVpatients, when used either alone or in combination with amelanoma vaccine gp100. Autoimmune side effects,while severe, are manageable. Vemurafenib targets mu-tated BRAF, a signaling molecule found in 50% of mela-nomas. The majority of patients respond rapidly and dra-matically; however, resistance to therapy develops usuallywithin the first 6 months. Trials using both therapies incombination are set to begin. External genital warts affect10% of adults in the USA with approximately 500,000new cases annually. Imiquimod 3.75% (Zyclara), a toll-like receptor 7 agonist, when used topically daily for 8weeks, produces significant responses in over half of maleand female patients with complete remission in a largenumber of those patients. Actinic keratoses are part of thebiologic continuum between photo-damaged skin andsquamous cell carcinoma. Ingenol mebutate gel (Picato)(0.015% applied daily � 3 days to the face/scalp; 0.05%el applied daily for 2 days to trunk/extremities) was re-ently approved for the topical therapy of actinic kerato-es. In addition to a direct cytotoxic effect, ingenol mebu-ate upregulates IL-8 from keratinocytes and endothelialells, resulting in massive neutrophil infiltration into thereatment areas. A new procedure involving harvestingbroblasts from skin biopsies, culturing and reinjectinghem into the dermis of cosmetic patients wanting a moreouthful appearance, was approved in 2011. The poten-ial for this therapy to be used outside the cosmetic realmill prove interesting over the next few years. Move overnabotulinumtoxin A (Botox). The marketplace now

as Abobotulinumtoxin A (Dysport approved in 2009)nd the recently approved Incobotulinumtoxin A (Xe-min approved in 2011). With equivalent efficacy andafety, looking more youthful is likely to cost less.—G.

artin, MD

JÖGREN’S SYNDROME UPDATE

jögren’s syndrome has received a good deal of attentionn the lay press recently because of high-profile individualsith the disease. Although most Sjögren’s patients can beanaged symptomatically with artificial tears and oraloisturizers, convincing evidence of effectiveness has

een shown for a number of useful medical therapies. For

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926 Proceedings of the 2012 rheumatology winter clinical symposia

ocular dryness, topical cyclosporine, administered as0.05% drops, is effective at reducing symptoms and im-proving objective measures of tear production. Two oralagents are available for treating both oral and ocular dry-ness. The muscarinic agonists pilocarpine and cevimelineimproved dry mouth and dry eyes in randomized, con-trolled trials. Hydroxycholoroquine has been used for sys-temic symptoms of Sjögren’s, particularly arthralgias, buthas only been tested in 2 small studies, and the resultswere inconclusive. Oral immunomodulatory agents, in-cluding steroids, cyclosporine, methotrexate, and azathio-prine, produced little or no benefit for sicca symptoms inprospective trials. Despite great interest in the use of bio-logic agents for severe or refractory Sjögren’s syndrome,etanercept and infliximab were ineffective in controlledtrials. Rituximab failed to improve stimulated salivaryflow, the primary endpoint in a small, controlled trial, butled to improvement in a number of secondary endpoints.Epratuzumab, the anti-CD22 antibody, improved sicca,fatigue, and laboratory parameters in a small, open-labelpilot study. The ideal role for B-cell-directed therapies inthe management of severe Sjögren’s syndrome remains tobe determined.—E. Ruderman

LATEST DEVELOPMENTS IN SYSTEMIC LUPUS

B-cell-targeted therapies: Similar to the recently approvedmonoclonal antibody (mAb) belimumab, there are 2products, tabalimumab, a mAb, and blisibimod, a pepti-body, that also target B-lymphocyte stimulator/B-cell ac-tivating factor (BLyS/BAFF). Unlike belimumab, bothcan bind membrane-bound as well as soluble BLyS, indi-cating that they may be more potent inhibitors. Largephase 2 and 3 randomized controlled trial (RCTs) withboth agents are underway. Another agent, atacicept,blocks both BLyS and a proliferation-inducing ligand(APRIL). Another approach is to focus on plasma cells byusing bortezomib, a proteasome inhibitor approved fortreatment of multiple myeloma. This agent induced apo-ptosis of short- and long-lived plasma cells by activationof the terminal unfolded protein response, decreased anti-dsDNA antibody titers, and ameliorated disease in 2 an-imal models of lupus nephritis. Last, epratuzumab is ahumanized mAb that binds the CD22 antigen on the

surface of B cells, resulting in internalization and down- t

regulation of the B-cell receptor. Administration ofepratuzumab resulted in a partial depletion of peripheralB cells in phase 2 RCTs, with efficacy demonstrated in the2400-mg-dose groups, and acceptable tolerability. Twolarge phase 3 RCTs are currently underway.

Cytokine-targeted therapies: Sifilimumab and Rontali-zumab are mAbs to interferon-� (IFN-�), thereby inhib-ting the assembly and internalization of the heterotrimerf ligand and IFN-� receptor. In a phase 2a RCT withifilimumab, sustained inhibition of the IFN-� signatureas demonstrated with a trend for decreased disease ac-

ivity. Two mAbs targeting IL-6 are in early RCTs inystemic lupus erythematosus (SLE): Sirukumab and PF-4236921, based on an open-label proof of concept studyith tocilizumab. Early trials are underway.Peptide immunomodulators: Lupuzor is a peptide

ragment analog based on residues 131 to 151 of Ui-70Kpliceosomal protein with a phosphorylated serine at po-ition 140 that induces IL-10 production by CD4 T cells.n a phase 2b RCT decreases in anti-dsDNA antibodyiters and early evidence of efficacy were demonstrated. Ahase 3 trial is currently underway.Edratide is a peptide based on the sequence of a heavy-

hain CDR of a human anti-dsDNA antibody that failedn a phase 2 RCT, but with data suggestive of efficacy afterurther analyses. It is currently under evaluation in a largerhase 2 trial. Two quinoline-3 carboxamides, laquinimodnd paquinimod (ABR-215757), are in early trials inLE.

This is an exciting era in drug development with manygents under evaluation in SLE. Use of responder indexesased on both the Selena SLEDAI and the BILAG instru-ents have facilitated assessment of efficacy in trials of

elimumab and epratuzumab and are planned to be usedn subsequent RCTs.— V. Strand, MD

ONCLUSIONS

here have been many recent exciting developments inheumatology. Rheumatologists must be kept abreast ofew diagnostic and therapeutic information across aumber of rheumatologic, autoimmune, and related con-itions. By doing so, they will help optimize outcomes for

heir patients.