Aschwanden, Markus

Bilecen, Deniz

Bongartz, Georg

Daikeler, Thomas

Huegli, Rolf W.

Jacobi, Bjoern

Karimi, Sasan

Lyo, John K.

Michel, Sandra

Partovi, Sasan

Rasmus, Matthias

Schulte, Anja-Carina

Staub, Daniel

Zipp, Lisa

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6 Jaffe IA. Induction of auto-immune syndromes by peni-cillamine therapy in rheumatoid arthritis and other dis-eases. Semin Immunopathol 1981;4:193207.7 Couto D, Ribeiro D, Frietas M, Gomes A, Lima JLFC,Fernandes E. Scavenging of reactive oxygen and nitrogenspecies by the prodrug sulfasalazine and its metabolites5-aminosalycylic acid and sulfapyridine. Redox Rep 2010;15:25967.Rheumatology 2013;52:579581doi:10.1093/rheumatology/kes176Advance Access publication 27 July 2012Alterations of skeletal muscle microcirculationdetected by blood oxygenation level-dependentMRI in a patient with granulomatosis withpolyangiitisSIR, Granulomatosis with polyangiitis (GPA) is a smallvessel vasculitis that is associated with cardiovasculardisease, which mainly determines the prognosis of GPApatients [1, 2]. Contradictory evidence has been publishedregarding accelerated atherosclerosis in GPA, whichmight cause cardiovascular morbidity [3, 4]. Blood oxy-genation level-dependent (BOLD) MRI of skeletal musclehas become a valuable tool for the assessment of vascu-lar pathologies such as atherosclerosis, diabetes mellitusand chronic compartment syndrome [57]. T2*-weightedMR signal of gradient-echo echo-planar imaging (EPI)sequences is sensitive to changes of oxyhaemoglobinconcentration in small pre- and post-capillary vessels [8].Here we present a case of a 73-year-old female GPA pa-tient who was treated in our rheumatology clinic owing tosevere myalgias. She had a 7-year history of GPA with naso-pharyngeal symptoms, haemoptysis, arthritis, dysesthe-sias and renal involvement. During her actual admission,laboratory tests revealed leucopenia of 2.6/nl (referencerange 3.510.0/nl), lymphopenia of 0.21/nl (0.93.3/nl), hae-matocrit 0.38 l/l (0.360.46 l/l), CRP 0.4 mg/l (<10 mg/l),BSG 10 mm/h (028 mm/h), ANCA 1 : 20 (<1 : 20),anti-MPO <2.5 U/ml (<5 U/ml) and anti-PR3 6 U/ml (<5U/ml). Her blood pressure was 130/70 mmHg. She had nohistory of hypertension, diabetes mellitus or hyperlipida-emia. Her peripheral pulse status was normal and shenever suffered from claudication. Recent maintenance im-munosuppressive medication consisted of 150 mgazathioprine and 10 mg prednisone daily. MRI measure-ments were indicated owing to severe myalgias of bothlegs and performed on a 3.0-T scanner (Verio, SiemensMedical Solutions, Erlangen, Germany). Informed consentwas obtained, and the study was approved by the localethics committee (Ethikkommission beider Basel). AT2-weighted sequence revealed no signs of local inflamma-tory activity of the calves. For BOLD imaging, a healthyfemale volunteer controlled for age, BMI and physical ac-tivity served as control after providing consent. A multi-echogradient-echo EPI sequence with fat suppression was usedwith a cuff compression paradigm as previously described[5, 9, 10]. Briefly, BOLD imaging was performed during thelast minute of a 300 s resting period, 180 s of ischaemia and400 s of reactive hyperaemia. Four axial slices (thickness5 mm, gap 2.5 mm) were positioned in the upper calf. Witheach excitation, four echo images with increasing effectiveecho times were acquired. Inflow (initial signal intensity, I0)and oxygenation (susceptibility, T2*) effects were sepa-rated by a pixel-by-pixel least-square fit of a monoexponen-tial decay to the signal intensities at the four different echotimes (TE14 of 9.3, 20.1, 31.0 and 41.5 ms) according toS(I0, T2*) = I0 exp(TE14/T2*). T2* maps were computed,supplemented with T1-reference images and ROIs placedin the soleus, gastrocnemius and peroneus, excludingpixels of bones and vessels (Fig. 1).(i) Absolute baseline T2* values were comparable be-tween the two individuals (patient 21.6 ms, control21.1 ms).(ii) Absolute and relative minimum ischaemic T2*values (T2*min) were substantially lower in the GPApatient (15.3 ms, 29.4%) than in the control(19.7 ms, 9.5%).(iii) Relative T2* decline after cuff compression[ischaemic declining slope (IDS)] was significantlysteeper in the GPA patient, when compared withthe healthy volunteer (4.1%/ms vs 1.0%/ms).(iv) Absolute and relative T2* peak values during react-ive hyperaemia (T2*max) were strongly reduced inthe patient (23.6 ms, +7.0% vs 25.0 ms, +18.4%).(v) Time to peak value (TTP), reflecting the time fromcuff deflation to T2*max, was similar between thetwo subjects (32 s vs 34 s).(vi) T2* end value (EV, reflecting medium T2* during thelast 10 s of measurement) was higher in the GPApatient compared with the control.These findings strongly suggest major perturbations ofskeletal muscle microcirculation in this GPA patient,revealed by skeletal muscle BOLD MRI. The lowerT2*min value in the patient might be explained byincreased oxygen consumption as control and patientshowed comparable baseline absolute T2* values, andthe IDS absolute value was substantially higher in the pa-tient. This might be a compensatory mechanism forchronic hypoxic conditions in patients with GPA. T2*maxdecrease could be explained by reduced blood flow inskeletal muscle microvessels, owing to small vessel vas-culitis. The underlying mechanisms of the detected BOLDalterations have to be interpreted with care owing to otherT2* influencing factors such as blood volume, haemato-crit, functional vascular status and metabolic changes [5,7]. Owing to the lack of reference methods for the meas-urement of perfusion or oxygenation, our findings remainmostly descriptive. However, the measured BOLD re-sponse in GPA is different from previous results in patientswith atherosclerosis that showed diminished ischaemicT2* decline and a prolonged TTP [5, 10]. This may indicatethat other mechanisms besides accelerated atheroscler-osis play an important role in the pathogenesis of skeletalmuscle microcirculation alterations in GPA. Of course,Letters to the Editorwww.rheumatology.oxfordjournals.org 579further studies with larger patient collectives are war-ranted to elucidate the underlying mechanisms of thedescribed BOLD signal alterations in GPA.Rheumatology key message. Alterations of skeletal muscle microcirculation inGPA can be revealed by BOLD MRI.Disclosure statement: M.R.’s institute has a scientific col-laboration with Siemens and an unrestricted researchfund from Bayer Health Care. G.B. has received unre-stricted grants from Bayer Healthcare, Switzerland andSiemens Medical Systems, Switzerland. All other authorshave declared no conflicts of interest.Bjoern Jacobi1,2, Anja-Carina Schulte1,Sasan Partovi1,3, Sandra Michel4, Sasan Karimi3,John K. Lyo3, Thomas Daikeler4,Markus Aschwanden5, Daniel Staub5, Lisa Zipp1,Matthias Rasmus6, Rolf W. Huegli1,Georg Bongartz6 and Deniz Bilecen11Department of Radiology, University Hospital Bruderholz,Bruderholz, Basel, Switzerland, 2Department of Hematology,Oncology and Rheumatology, University of Heidelberg,Heidelberg, Germany, 3Department of Radiology, Section ofNeuroradiology, Memorial Sloan-Kettering Cancer Center,New York, NY, USA, 4Department of Rheumatology,5Department of Angiology and 6Department of Radiology,University Hospital Basel, Basel, Switzerland.Accepted 25 May 2012Correspondence to: Deniz Bilecen, Department of Radiology,University Hospital Bruderholz, 4101 Bruderholz, Basel,Switzerland. E-mail: deniz.bilecen@unibas.chReferences1 Kallenberg CG. Pathogenesis of ANCA-associated vas-culitides. Ann Rheum Dis 2011;70(Suppl 1):i5963.2 Morelli S, Gurgo Di Castelmenardo AM, Conti F et al.Cardiac involvement in patients with Wegener’s granulo-matosis. Rheumatol Int 2000;19:20912.3 de Leeuw K, Sanders JS, Stegeman C et al. Acceleratedatherosclerosis in patients with Wegener’s granulomato-sis. Ann Rheum Dis 2005;64:7539.4 Tervaert JW. Translational mini-review series on immun-ology of vascular disease: accelerated atherosclerosis invasculitis. Clin Exp Immunol 2009;156:37785.5 Ledermann HP, Schulte AC, Heidecker HG et al. Bloodoxygenation level-dependent magnetic resonanceFIG. 1 BOLD MRI in a patient with GPA.Anatomical reference image (T1) of the examined upper calf region (A) and the corresponding T2* maps (B). T2* timecourses (C) of the left leg in the patient with GPA (red) and the healthy volunteer (blue). A steeper signal decline to asignificantly lower T2*min could be detected in the GPA patient. After cuff deflation, T2*max was extensively reduced in thepatient and signal decline was slower than in the control.Letters to the Editor580 www.rheumatology.oxfordjournals.orgimaging of the skeletal muscle in patients with periph-eral arterial occlusive disease. Circulation 2006;113:292935.6 Sanchez OA, Copenhaver EA, Chance MA et al.Postmaximal contraction blood volume responses areblunted in obese and type 2 diabetic subjects in amuscle-specific manner. Am J Physiol Heart Circ Physiol2011;301:H41827.7 Noseworthy MD, Davis AD, Elzibak AH. Advanced MRimaging techniques for skeletal muscle evaluation. SeminMusculoskelet Radiol 2010;14:25768.8 Noseworthy MD, Bulte DP, Alfonsi J. BOLD magneticresonance imaging of skeletal muscle. SeminMusculoskelet Radiol 2003;7:30715.9 Ledermann HP, Heidecker HG, Schulte AC et al. Calfmuscles imaged at BOLD MR: correlation with TcPO2 andflowmetry measurements during ischemia and reactivehyperemia—initial experience. Radiology 2006;241:47784.10 Potthast S, Schulte A, Kos S, Aschwanden M, Bilecen D.Blood oxygenation level-dependent MRI of the skeletalmuscle during ischemia in patients with peripheral arterialocclusive disease. Rofo 2009;181:115761.Rheumatology 2013;52:581582doi:10.1093/rheumatology/kes168Advance Access publication 9 August 2012Vasculitis following HPV immunizationSir, we report two cases of vasculitis following HPVimmunization, which has not previously been described.Case 1, a 15-year-old girl, presented with three small pur-puric lesions on the lower left leg 3 days after the seconddose of the HPV vaccine. These progressed over the next2 weeks to a florid purpuric rash affecting the lower limbs,buttocks and extensor surfaces of both elbows. She wasafebrile, with no abdominal pain or arthritis; blood pres-sure was normal. Urinalysis showed +++ of blood but noprotein or nitrates.A diagnosis of probable HenochScho¨nlein purpura(HSP) was made. Two weeks later she re-presented withextensive generalized vasculitic rash, soft tissue swellingsof both ankles and forearms, arthralgia, lethargy and epi-staxis. Laboratory tests were normal (CRP <5 mg/l, ESR25 mm/h). Full autoantibody screen was negative; com-plement (C3, C4) and serum immunoglobulins werenormal. Skin biopsy showed a mild perivascular lympho-cytic inflammatory cell infiltrate and occasional eosinophilinterstitial infiltrate. The swellings and cutaneous vasculitisinitially improved with oral prednisolone and antibioticsbut deteriorated dramatically as CSs were discontinued.Ten weeks after the initial presentation, the vasculitic rashwas re-biopsied, revealing a leukocytoclastic vasculitis(LV); immunofluorescence was negative for IgA depos-ition. Treatment with prednisolone (0.5 mg/kg/day) andcolchicine (1500 mg/day) was started. Azathioprine wassubsequently added as an additional steroid-sparingagent, which led to resolution of the vasculitis and suc-cessful steroid taper.Case 2 was diagnosed with HSP at the age of 13 yearswith typical cutaneous vasculitis, abdominal pain, arthral-gia and microscopic haematuria. Laboratory tests includ-ing renal function, inflammatory parameters and fullautoimmune workup were normal. IgA was elevated at3.54 g/l (0.82.8). Infectious workup was negative. Overthe next 2 years there was gradual resolution with recur-rent vasculitic skin rash lasting for a few days mainly afterintercurrent infections. Aged 15 years, with the vasculitisin remission, the first dose of the HPV bivalent vaccinewas given. Three days later she had a severe flare of cu-taneous vasculitis. Laboratory tests were as previouslydocumented. Skin biopsy showed endothelial cell hyper-plasia and neutrophil infiltration into the vessels within thedermis, compatible with acute cutaneous vasculitis.Immunofluorescence for IgA, IgG, IgM, C1q, C3 andfibrin was negative and consistent with cutaneous LV [1].To the best of our knowledge, these are the firstreports of vasculitis associated with the HPV vaccine.Both cases presented with a small-size vessel vasculitispredominantly affecting the skin soon after HPV vaccin-ation, the first being a de novo isolated cutaneous LV andthe second a vasculitis recurrence. Immunization withHPV vaccine has the potential to decrease the globalmorbidity and mortality of HPV-related disease, includingcervical cancer, and thus represents a major break-through in medicine [2]. As HPV 16 and 18 are involvedin the pathogenesis of 7075% of all cases of invasivecervical cancer, vaccination in this context offers aneffective means of primary cancer prevention [3] and isonly the second vaccine that has been licensed with thisindication [4].Overall the balance between the risks and benefits ofthe HPV vaccine is overwhelmingly positive. A recentlypublished pooled analysis of 11 clinical trials showed nosignificant differences between the vaccine and thecontrol group regarding severe side effects or the devel-opment of chronic illnesses including autoimmune dis-eases [5].LV is the most frequent form of vasculitis affecting theskin, involving small vessels but particularly post-capillaryvenules. In many cases, LV is caused by large immunecomplexes deposited at the vessel wall, which can beeither IgA (as in HSP) or contain IgM or IgG. LV can alsobe secondary to ANCA-associated vasculitis and canoccur without immune complex deposition [6]. The failureto demonstrate IgA deposits by immunofluorescence onskin biopsy makes these cases better classified as hyper-sensitivity cutaneous LV despite the initial presumptiveclinical diagnosis of HSP [7].Several infectious agents and drugs have been incon-clusively identified as possible infective triggers ofhypersensitivity LV. In our reported cases, there wasno history of preceding infection, and the strong tem-poral relationship between the administration of the bi-valent HPV vaccine and the development of vasculitiswas notable.Letters to the Editorwww.rheumatology.oxfordjournals.org 581

Alterations of skeletal muscle microcirculation detected by blood oxygenation level-dependent MRI in a patient with granulomatosis with polyangiitis

Alterations of skeletal muscle microcirculation detected by blood oxygenation level-dependent MRI in a patient with granulomatosis with polyangiitis

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