Editorial

Joint Bone Spine 74 (2007) 316e318

http://france.elsevier.com/direct/BONSOI/

Biologics in the treatment of primary inflammatory myositis

Keywords: Myositis; TNF antagonists; Rituximab; Anakinra

The term ‘‘primary myositis’’ encompasses a group ofconditions in which the primary pathological process is in-flammation within the skeletal muscle. Their presentation isprotean and their management often challenging. The adventof biologicals has generated hope for improved outcomes.

The Bohan and Peter classification of myositis into 5groups based on clinical criteria has been replaced with clas-sification into 3 groups based on the histological appearanceand immunohistochemical characteristics of the muscle bi-opsy. The 3 groups are dermatomyositis (DM), polymyositis(PM), and inclusion-body myositis (IBM). In addition, a num-ber of distinctive patterns have been identified [1].

The low prevalence of primary myositis, about 6/100,000,is a major obstacle to controlled treatment trials. Overall mor-tality in untreated primary myositis (without cancer) is 70%.The 5-year survival rate with glucocorticoid therapy is 90%.Several factors of prognostic significance have been identified[2]. Progression to chronic disease or persistence of functionalimpairment is common. A full recovery is achieved in onlyabout half the patients with DM or PM. The adverse events in-duced by glucocorticoid and immunosuppressant treatment in-fluence the overall prognosis.

Improved understanding of the immune disorders that un-derlie primary myositis has led to the use of immunomodulat-ing and biological agents. In brief [1], DM is a humorallymediated vasculopathy in which B-cell and CD4þ T-cell infil-trates are found in a perivascular distribution, together withcomplement deposits. PM, in contrast, is a cell-mediated dis-ease characterized by CD8þ T-cell endomysial infiltrates.Muscle cells express Class I HLA antigens, and inflammatorycell infiltrates produce cytokines (INF-g and TNFa), which in-duce the expression of HLA antigens and adhesion molecules.In addition, cytokines exert direct toxic effects on muscle. Se-rum levels of type I and type II soluble TNF receptor are ele-vated in patients with active DM/PM [2].

High-dose glucocorticoid therapy is the mainstay of thetreatment of DM/PM. About 70% of patients respond initially

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[3]. The dosage is then tapered according to the clinical responseand serum creatine-kinase level. The minimum effective dosageis usually continued for several years. Primary or secondaryresistance to glucocorticoid therapy, intolerance, or glucocorti-coid dependency develops in 30%e50% of patients, requiringa switch to immunosuppressant therapy (methotrexate, cyclo-sporine, or mycophenolate mofetil). Studies of immunosuppres-sant agents, most of which used an open-label design, showedvariable results. Intravenous immunoglobulins may be used inpatients who fail to respond to glucocorticoid therapy.

Given the limited effectiveness of conventional therapeuticagents and the pathogenic mechanisms underlying DM/PM,treatment with biologics is generating interest. Most of thebiologics studied to date targeted either TNFa or the B cell.Anecdotal case reports and small case-series have beenreported.

1. TNFa antagonists

Data on DM/PM treated with TNFa antagonists are avail-able for 27 patients, as anecdotal case reports [4e15] or smallseries (2 cases [6,7], 8 cases [16], and 5 cases [17]). Of these27 patients, 14 had DM, 11 PM, and 2 orbital myositis. Dis-ease duration was usually several years, and most patientshad failed to respond to glucocorticoid and immunosuppres-sant therapy; in 3 patients, however, TNFa antagonists weregiven as first-line therapy [7,17]. Infliximab was used in 13 pa-tients (3e10 mg/kg/infusion), etanercept in 12 patients, andadalimumab in 2 patients. Follow-up was only 2e15 months.Early improvements in the clinical manifestations and enzymeactivities were noted in 16 patients. Escape phenomenondeveloped in 2 patients, both on infliximab [8]. A partialresponse was obtained in 2 patients [7,16]. In 2 patients, therewas no response [16], and in 5 patients with DM the diseaseworsened during etanercept therapy [17].

Adverse events included candidal esophagitis in 2 patients[16]; fatal infection in 2 patients [6,11]; and 1 case each of

d.

317Editorial / Joint Bone Spine 74 (2007) 316e318

cardiac event [16], lymphoma [12], and splenic tumor [16].However, these events may have been caused by abnormalitiesassociated with DM/PM or prior immunosuppressant therapy,which was often used for many years. The development ofprimary myositis during TNFa antagonist therapy has beenreported in 2 patients: PM developed in 1 patient after thesixth infliximab infusion for rheumatoid arthritis [18] andorbital myositis occurred during etanercept therapy in theother patient [19].

2. Anti-B-cell therapy

Rituximab, a monoclonal antibody against CD20, was usedin 13 published cases of primary myositis. The results are de-scribed in small case-series (7 cases of DM, including 3 withno response to etanercept [20]; and 2 cases of PM plus 1 caseof DM [21]) or as anecdotal case-reports (3 patients, including2 with anti Jo-1 antibodies [22e25] with a total of 9 cases ofDM). Mean follow-up was 12 months. The dosage rangedfrom 100 mg/m2 to 1000 mg per infusion and the number ofinfusions from 2 to 6 (at 2-week intervals). These variationscomplicate the interpretation of the results. Nevertheless, aninitial improvement was observed consistently. In some cases,the clinical improvement occurred in parallel with the drop inB-cell counts. In 7 patients, a relapse after 6 months requireda further treatment cycle [20,21,23]. The safety profile wasacceptable. Sinusitis requiring drainage developed in 1 patient[23].

3. Anti-IL-1 therapy

IL-1 is another cytokine involved in the pathogenesis ofDM/PM [25,26]. However, IL-1 inhibition seems less effectivethan TNFa inhibition [25]. In a patient with lupus myositis,anakinra (an IL-1-receptor antagonist) failed to improve themuscle involvement [27].

4. Inclusion-body myositis

Etanercept was used in 9 patients with inclusion-bodymyositis. No difference in efficacy was found compared toa historical control group given conventional treatment. How-ever, the improvement in grip strength was slightly larger withetanercept [28].

6. Conclusion

Data on the effects of biologicals in patients with primarymyositis are just beginning to emerge, and caution is thereforein order. There is no conclusive proof to date that biologicalsare effective in primary myositis. TNFa antagonists were in-consistently effective in the short term and their effects weretransient in some cases. In addition, their safety profile in pa-tients with the immune disorders that characterize primarymyositis deserve careful consideration. Although rituximabseems to hold promise, most notably in patients with DM,available data are too scarce for definitive conclusions.

Controlled, multicenter, long-term studies of well-standard-ized treatment regimens are needed.

References

[1] Eymard B. Polymyosite, dermatomyosite, myosite a inclusions, aspects

nosologiques. Presse Med 2003;32:1556e67.

[2] Shimizu T, Tomita Y, Son K, Nishinarita S, Sawada S, Horie T. Elevation

of serum soluble tumour necrosis factor receptors in patients with poly-

myositis and dermatomyositis. Clin Rheumatol 2000;19:352e9.

[3] Cherin P. Traitement des myopathies inflammatoires. Presse Med

2003;32:1668e75.

[4] Adams AB, Kazim M, Lehman TJ. Treatment of orbital myositis with

adalimumab (Humira). J Rheumatol 2005;32:1374e5.

[5] Anandacoomarasamy A, Howe G, Manolios N. Advanced refractory poly-

myositis responding to infliximab. Rheumatology (Oxford) 2005;44:562e3.

[6] Dold S, Justiniano ME, Marquez J, Espinoza LR. Treatment of early and

refractory dermatomyositis with infliximab: a report of two cases. Clin

Rheumatol, 2006 May 31; [Epub ahead of print].

[7] Hengstman GJ, van den Hoogen FH, Barrera P, Netea MG, Pieterse A,

van de Putte LB, et al. Successful treatment of dermatomyositis and pol-

ymyositis with anti-tumor-necrosis-factor-alpha: preliminary observa-

tions. Eur Neurol 2003;50:10e5.

[8] Hengstman GJ, van den Hoogen FH, van Engelen BG. Treatment of der-

matomyositis and polymyositis with anti-tumor necrosis factor-alpha:

long-term follow-up. Eur Neurol 2004;52:61e3.

[9] Korkmaz C, Temiz G, Cetinbas F, Buyukkidan B. Successful treatment of

alveolar hypoventilation due to dermatomyositis with anti-tumour necro-

sis factor-alpha. Rheumatology (Oxford) 2004;43:937e8.

[10] Labioche I, Liozon E, Weschler B, Loustaud-Ratti V, Soria P, Vidal E.

Refractory polymyositis responding to infliximab: extended follow-up.

Rheumatology (Oxford) 2004;43:531e2.

[11] Marie I, Heliot P, Roussel F, Herve F, Muir JF, Levesque H. Fatal Myco-

bacterium peregrinum pneumonia in refractory polymyositis treated with

infliximab. Rheumatology (Oxford) 2005;44:1201e2.

[12] Roddy E, Courtney PA, Morris A. Non-Hodgkin’s lymphoma in a patient

with refractory dermatomyositis which had been treated with infliximab.

Rheumatology (Oxford) 2002;41:1194e5.

[13] Selva-O’Callaghan A, Martinez-Costa X, Solans-Laque R, Mauri M,

Capdevila JA, Vilardell-Tarres M. Refractory adult dermatomyositis

with pneumatosis cystoides intestinalis treated with Infliximab. Rheuma-

tology (Oxford) 2004;43:1196e7.

[14] Sprott H, Glatzel M, Michel BA. Treatment of myositis with etanercept

(enbrel), a recombinant human soluble fusion protein of TNF-alpha type

II receptor and IgG1. Rheumatology (Oxford) 2004;43:524e6.

[15] Uthman I, El-Sayad J. Refractory polymyositis responding to Infliximab.

Rheumatology (Oxford) 2004;43:1198e9.

[16] Efthimiou P, Schwartzman S, Kagen LJ. Possible role for tumour necro-

sis factor inhibitors in the treatment of resistant dermatomyositis and pol-

ymyositis: a retrospective study of eight patients. Ann Rheum Dis

2006;65:1233e6.

[17] Iannone F, Sciosca C, Falappone PCF, Covelli M, Lapadula G. Use of

etanercept in the treatment of dermatomyositis: a case series. J Rheuma-

tol 2006;33:1802e4.

[18] Musial J, Undas A, Celinska-Lowenhoff M. Polymyositis associated with

infliximab treatment for rheumatoid arthritis. Rheumatology (Oxford)

2003;42:1566e8.

[19] Caramaschi P, Biasi D, Carletto A, Bambara LM. Orbital myositis in

a rheumatoid arthritis patient during etanercept treatment. Clin Exp

Rheumatol 2003;21:136e7.

[20] Levine TD. Rituximab in the treatment of dermatomyositis: an open-label

pilot study. Arthritis Rheum 2005;52:601e7.

[21] Noss EH, Hausner-Sypek DL, Weinblatt ME. Rituximab as therapy for

refractory polymyositis and dermatomyositis. J Rheumatol 2006;33:

1021e6.

318 Editorial / Joint Bone Spine 74 (2007) 316e318

[22] Lambotte O, Kotb R, Maigne G, Blanc FX, Goujard C, Delfraissy JF.

Efficacy of rituximab in refractory polymyositis. J Rheumatol

2005;32:1369e70.

[23] Brulhart L, Waldburger JM, Gabay C. Rituximab in the treatment of anti-

synthetase syndrome. Ann Rheum Dis 2006;65:974e5.

[24] Chiappetta N, Steier J, Gruber B. Rituximab in the treatment of refrac-

tory dermatomyositis. J Clin Rheumatol 2005;11:264e6.

[25] Chevrel G, Granet C, Miossec P. Contribution of tumour necrosis factor

alpha and interleukin (IL) 1beta to IL6 production, NF-kappaB nuclear

translocation, and class I MHC expression in muscle cells: in vitro

regulation with specific cytokine inhibitors. Ann Rheum Dis 2005;64:

1257e62.

[26] Son K, Tomita Y, Shimizu T, Nishinarita S, Sawada S, Horie T. Abnor-

mal IL-1 receptor antagonist production in patients with polymyositis

and dermatomyositis. Intern Med 2000;39:128e35.

[27] Moosig F, Zeuner R, Renk C, Schroder JO. IL-1RA in refractory sys-

temic lupus erythematosus. Lupus 2004;13:605e6.

[28] Barohn RJ, Herbelin L, Kissel JT, King W, McVey AL, Saperstein DS,

et al. Pilot trial of etanercept in the treatment of inclusion-body myositis.

Neurology 2006;66:S123e4.

Daniel WendlingRheumatology Department, Minjoz Teaching Hospital,

Boulevard Fleming, 25030 Besancon cedex,France

Corresponding author. Tel.:þ33 (0) 3 81 66 82 41;fax: þ33 (0) 3 81 66 86 86.

E-mail address: dwendling@chu-besancon.fr

30 August 2006

Available online 24 May 2007