by stimulated inflammatory cells including macrophages (4).Inhibition of cytokine release, most notably interleukin-1 (IL-1)inhibition, may be a key phenomenon. A recent study establisheda direct role for crystals in inflammasome activation, whichpromotes the release of active IL-1 from proIL-1 (5).

These properties of MTX are consistent with thera-peutic effects in CPDD, most notably in patients with re-current polyarthritis simulating rheumatoid arthritis. AlthoughChollet-Janin et al observed a favorable clinical responseto MTX therapy in their 5 patients, none of our 3 patientsresponded. These data strongly support a need for a ran-domized, placebo-controlled study. The MTX dose, treat-ment duration, patient selection criteria, and responsecriteria would require careful attention when designing thestudy. The risk/benefit ratio of MTX requires close monitoringin patients with this non–life-threatening disease.

Thi Huyen Tran Doan, MDXavier Chevalier, MD, PhDHenri Mondor Teaching HospitalParis XII UniversityCreteil, FranceJean Marie Leparc, MDAmbroise Pare Teaching HospitalBoulogne Billancourt, FrancePascal Richette, MD, PhDThomas Bardin, MDLariboisiere Teaching HospitalParis VII UniversityRheumatology FederationParis, FranceRomain Forestier, MDRheumatology and Spa Therapy Research CenterAix les Bains, France

on behalf of the French Society for RheumatologyOsteoarthritis Section

1. Chollet-Janin A, Finckh A, Dudler J, Guerne PA. Methotrexate asan alternative therapy for chronic calcium pyrophosphate deposi-tion disease: an exploratory analysis. Arthritis Rheum 2007;56:688–92.

2. Wise CM. Crystal-associated arthritis in the elderly. Rheum DisClin North Am 2007;33:33–55.

3. Cronstein BN, Naime D, Ostad E. The antiinflammatory mecha-nism of methotrexate: increased adenosine release at inflamed sitesdiminishes leukocyte accumulation in an in vivo model of inflam-mation. J Clin Invest 1993;92:2675–82.

4. Morabito L, Montesinos MC, Schreibman DM, Balter L, Thomp-son LF, Resta R, et al. Methotrexate and sulfasalazine promoteadenosine release by a mechanism that requires ecto-5�-nucleoti-dase-mediated conversion of adenine nucleotides. J Clin Invest1998;101:295–300.

5. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome.Nature 2006;440:237–41.

DOI 10.1002/art.23587

Intravenous immunoglobulin in Wegener’sgranulomatosis and microscopic polyangiitis

To the Editor:We read with interest the recent study by Martinez et

al (Martinez V, Cohen P, Pagnoux C, Vinzio S, Mahr A,

Mouthon L, et al. Intravenous immunoglobulins for relapses ofsystemic vasculitides associated with antineutrophil cyto-plasmic autoantibodies: results of a multicenter, prospective,open-label study of twenty-two patients. Arthritis Rheum2008;58:308–17), in which they explored the safety and efficacyof intravenous immunoglobulins (IVIGs) in an open-labelstudy that enrolled small numbers of patients with 2 differentdiseases, Wegener’s granulomatosis (WG; n � 19) and micro-scopic polyangiitis (MPA; n � 3). Contrary to the authors’statement that, “For decades, IVIGs have shown potent ther-apeutic efficacy in patients with ANCA [antineutrophil cyto-plasmic autoantibody]–positive vasculitides,” the issue of effi-cacy has never been clearly resolved. Prior studies have beenlimited by evaluating small numbers of patients in whommultiple treatment variables were changed, confounding inter-pretation of the results. Because of this, other investigatorshave concluded that the utility of IVIGs in WG and MPA willnot be clearly established without randomized controlled trialsfor which clinical end points are firmly delineated, and inwhich the addition or increase in the dose of other immuno-suppressive agents is not allowed.

Based on the experience from their study, Martinezand associates concluded that IVIGs can be included in atherapeutic strategy with other drugs used to treat relapses ofWG or MPA. In reviewing the study methods and results fromtheir trial, however, we had difficulty reaching these conclu-sions or defining what, if any, role IVIGs should have in thetreatment of these diseases.

Martinez et al enrolled 22 patients who were treatedwith IVIGs at a dosage of 0.5 gm/kg/day for 4 consecutive dayseach month for 6 months. Although Birmingham VasculitisActivity Scores were provided, the spectrum and severity ofdisease activity were unclear, which takes on added importancein light of the concomitant treatments permitted in this study.Among the 22 patients, 21 were treated with glucocorticoids(GCs) during the first 3 weeks, including 6 patients whoreceived pulse methylprednisolone. The dose of GCs for anygiven patient was left to each physician’s discretion. Furtherconfounding assessment of the response to IVIGs was the useof non-GC immunosuppressive agents in 18 patients. Therewere 5 agents of this type, and the duration of use for eachagent prior to the initiation of IVIGs was unclear. In addition,cotrimoxazole was being given to 12 patients with WG to“prevent relapse.” Regardless of what outcomes followed, itwould be unclear what agent or combination of agents wasresponsible for the observed salutary or adverse affects.

The authors’ results raise further questions about theefficacy of IVIGs, given that within the first 6 months, whilethe patients were still receiving IVIGs, 14% experienced arelapse, and by 9 months of followup, 33% of the patients hadexperienced a relapse. In 1 patient with WG, renal insuffi-ciency developed. Moderate transient adverse effects werereported in 32% of patients. The decision to halt the study wasbased on an interim analysis in which the objective was to haveat least 20% of patients with complete remission or 50% withpartial remission at month 9 of followup. These values are farbelow what is expected for standard therapies, making itchallenging to determine the presence of any efficacy signal.

Although the authors refer to Churg-Strauss syndromein the introduction, no patients with Churg-Strauss syndromewere enrolled in their study. Because the investigators included

LETTERS 2211

Churg-Strauss syndrome as part of their definition of ANCA-associated vasculitis, the title is misleading. This highlights oneof the many problems with the terminology “ANCA-associatedvasculitis” and the advantages of considering these as separatediseases, particularly within therapeutic trials.

We do not think that these data lend any additionalsupport for the use of IVIGs in WG and MPA. Althoughrandomized, double-blind, controlled studies would be neededto determine effectiveness, the available data raise questions asto whether IVIG treatment warrants additional investigation inplace of emerging therapies.

Carol A. Langford, MD, MHSGary S. Hoffman, MDCleveland ClinicCleveland, OH

DOI 10.1002/art.23586

Reply

To the Editor:We fully agree with the comments of Drs. Langford

and Hoffman concerning the major advantages of prospective,randomized, controlled trials to demonstrate clearly the indi-cations of drugs. However, the French Vasculitis Study Group,which has, to date, organized the majority of such trials insystemic necrotizing vasculitides, also has extensive experienceassessing the feasibility of such studies when they target aselected population of patients.

Our intent was to treat patients with ANCA-positivevasculitides refractory to several lines of immunosuppressantswho did not have severe renal insufficiency. A randomizedstudy in this setting, even organized on an international basis,would probably have been unrealizable because of the rarity ofthis precise situation. Therefore, based on the results of severalstudies, including one randomized trial, that explored theindications for IVIGs, we decided to focus on a subgroup ofpatients whose treatment was considered to be at an impasseand to undertake a prospective, open-label, nonrandomizedstudy. For this group of patients, an add-on study was the onlyethical approach, because we considered that stopping allother treatments would not have been reasonable.

We authorized an increase of the steroid dose for only3 weeks, with the objective to return to the prerelapse dose.Because the first end point of the study was to obtain remissionby 9 months, i.e., 3 months after stopping IVIGs, and becausewe also analyzed outcomes at 12 months and 24 months, weconsidered it unlikely that remission could have been the conse-quence of this temporary intensification of steroid therapy.

Cotrimoxazole (400/80 mg of trimethoprim/sulfamethoxazole) was prescribed to prevent Pneumocystisjiroveci pneumonia. This dose has never been described in theliterature or was found in our personal experience to have acurative impact on ANCA-positive vasculitides, alone or com-bined with other drugs, and, more specifically, in patients withsevere or relapsing disease. Cotrimoxazole (800/160 mg oftrimethoprim/sulfamethoxazole) to prevent relapses was pre-scribed to 12 patients before relapse occurred and IVIGs wereadministered.

Our intention was to include patients with Churg-Strauss syndrome, but no candidates became available. It must

be kept in mind that all of these prospective trials are nowregistered in American or European governmental Web sites,so the protocol could not be modified a posteriori and shouldbe published under Methods in the manuscript as it wasinitially conceived. However, the absence of patients withChurg-Strauss syndrome in this study in no way modifies theresults. The title is not misleading, because patients with 1 of 2major ANCA-associated vasculitides—WG or MPA—wereenrolled for treatment.

The main clinical characteristics of the patients, shownin Table 1 of our study, are explicit: the frequency of clinicalmanifestations at the time of inclusion, according to theKarnofsky Index, the BVAS, and lung, kidney, and ear, nose,and throat involvement, as well as the description of inclusioncriteria seem sufficient to understand the severity of thevasculitides considered.

We agree that our objectives—to obtain 20% completeremissions or 50% partial remissions—were not sufficientlyambitious. However, when we designed the study, we werefully aware that we would be confronted with difficult-to-treatpatients; in light of the excellent results obtained after 6 IVIGinfusions (72.7% remission at 6 months), these retrospectivecriticisms seem counterproductive.

Concerning the patient with WG in whom renal insuf-ficiency developed in the days following the first IVIG infu-sion, we believe that it occurred too early to be attributed tothe lack of IVIG efficacy. Moreover, because we conducted anintent-to-treat analysis, the patient was retained in the cohort,unlike the data collected in many protocols that are analyzedonly after a predefined number of drug administrations hadbeen given and a certain amount of time had elapsed.

All physicians involved in the treatment of ANCA-positive vasculitides are confronted with patients who experi-ence a relapse or do not respond to treatment. The time hasprobably come to change the standard of care and to move on,as has been largely done in the fields of transplantation,oncology, hematology, infectious diseases, and rheumatology,to a therapeutic approach combining drugs with the aim ofincreasing efficacy while limiting side effects. In our opinion,the trial we conducted reached that objective, and we thinkthat treatment with IVIGs, when added to ongoing ineffectiveregimens, could help to resolve some difficult or intractablesituations.

Loıc Guillevin, MDValerie Martinez, MD, PhDHopital CochinAssistance Publique Hopitaux de ParisUniversite Paris DescartesParis, Franceon behalf of the French Vasculitis Study Group

DOI 10.1002/art.23688

Seronegative disease after inadequate therapy in Lymearthritis: comment on the article by Kannianet al

To the Editor:The recent article by Kannian et al regarding antibody

responses in Lyme arthritis (1) again provides important

2212 LETTERS