EFFECTIVENESS OF PHARMACOLOGICAL INTERVENTIONS FOR THE TREATMENT OF PAEDIATRIC

(AND ADULT) POLYARTERITIS NODOSA

FEEDBACK FOLLOWING PRELIMINARY SEARCH

QUERY REF: PAED-002

Received: 14.12.2010 Feedback to CSG: 31.01.2011(due), 21.01.2011(sent)

SEARCH METHODOLOGY
The content of this feedback report refers only to the most relevant material located under each
of the evidence headings and is drawn predominantly from author abstracts or research
recommendations within Guidelines. The question is posed in the context of controlled and
uncontrolled trials exploring the effectiveness of pharmacological interventions in the context of
paediatric (and adult) patients with polyarteritis nodosa (PAN). This report therefore focuses on
material that makes a clear connection between pharmacological interventions and polyarteritis
nodosa. Studies are restricted to those published over the last five years (2006-January 2011
inclusive). Further details of all the studies included in this report are shown in the appendix,
sorted by report section and author name.

Criteria used (PICO):

Who? (population)
Studies involving individuals of 18 years of age and under diagnosed with polyarteritis nodosa.

What? (intervention/exposure/measure)
Pharmacological interventions

Comparison
Other pharmacological interventions

What is measured? What are the outcomes?

Morbidity; mortality.

Location and setting

No specific requirements

Exclusion Criteria
No specific criteria

Non-English language guidelines, recommendations, systematic reviews, overviews and clinical

opinions. However, non-English language primary research articles with English abstracts were
included, see Section D: Primary Research.

© Arthritis Research UK 2011

Databases Searched
NHS Evidence: Health Information Resources (Bandolier, UK Database of Uncertainties about the
Effects of Treatments [DUETS], National Library of Guidelines including NICE Guidance,
International Guidelines, Clinical Knowledge Summaries, NHS Evidence Specialist Collections
[Musculoskeletal]); TRIP database; Centre for Reviews and Dissemination (DARE, NHS EED and
HTA); Cochrane Database of Systematic Reviews; EMBASE; MEDLINE; ISRCTN Register; Medical
Research Council: Clinical Trials Unit; UK Clinical Research Network Study Portfolio; NIH records on
ClinicalTrials.gov; Nederlands Trial Register; German Clinical Trials Register; Australian New
Zealand Clinical Trials Registry.

Citation tracking was also used to locate relevant articles.

Types of Study
Head-to-head, controlled or outcome trials, and case studies.

Keywords searched
Polyarteritis [nodosa]; periarteritis nodosa; panartertitis nodosa; Kussmaul[-Maier] disease; drug
therapy; drug treatment (including dt.fs); Prednisolone; Methylprednisolone; azathioprine;
mycophenolate mofetil; corticosteroid; cyclophosphamide.

Keywords and phrases were used separately or in combination; truncation was used where
possible/applicable. MESH terms were also included.

Date limits
2006 to date i.e. previous 5 years.

Summary of available evidence

EVIDENCE TYPE INCLUDED IN FEEDBACK

A Evidence Summaries 1 (adult)
B Systematic Reviews (and non-systematic reviews) 2 (paediatric [& adult])1
C Clinical Trial Registries (Current and Closed) 9 (adult & paediatric)
D Primary Research 31 (paediatric)1,2
E Overviews and expert opinions N/A
F Intellectual Property Office N/A

1
Of which, one article presents both a review and case report.
2
93 articles refer to adult PAN: these are not detailed in this report, but a reference list is provided in the
appendix (see section D.2)

2
RESULTS
A: Good Quality Evidence Summaries (including guidelines)

No recent evidence summaries (2006-date) specifically address paediatric polyarteritis nodosa or

include polyarteritis in broader summaries of vasculitis or rheumatic disease. Similarly no
publications were identified which focused on polyarteritis nodosa in adults, however, there were
broader recommendations for the management of primary small and medium vessel vasculitis
including PAN (Mukhtyar et al., 2009: see Appendix Section A). These include the use of high-dose
glucocorticosteroids, or combination glucocorticosteroids and cyclophosphamide to induce
remission; the use of low-dose glucocorticosteroids combined with azathioprine, leflunomide or
methotrexate therapy for remission-maintenance; that alternative immunomodulatory treatment
is available, following referral to expert centres, for patients not achieving remission or relapse on
maximum doses of standard therapy; hepatitis B-associated PAN be treated with combination
antiviral therapy, glucocorticosteroids and plasma exchange.

B: Systematic Reviews

This section includes meta-analyses, systematic reviews and evidence reviews where little specific
detail of the review methodology is given (i.e. non-systematic review).

Two reviews were identified. One review specifically examines case reports and case studies of
paediatric cutaneous PAN (Bansal & Houghton, 2010) and concludes that a majority of children
respond well to corticosteroid therapy, in those that respond poorly the addition of DMARD
and/or biologics is necessary. The need for a central vasculitis disease registry to inform clinical
practice was also highlighted. The second review focuses on mortality in systemic vasculitis (adults
and children) (Phillip & Luqmani, 2008): For PAN survival rates are approximately 75-80%, and 83%
for hepatitis B-associated PAN; death is primarily associated with active disease and poor
prognosis factors include increasing age and cardiac, CNS or gastrointestinal involvement. It
concludes that whilst improved management has decreased mortality, there are still significant
fatal complications of current treatment regimes.

A further review, not detailed in the appendix, may be of interest which focuses on Macrophage
migration inhibitory factor as a therapeutic target for autoinflammatory conditions (Greven, Leng,
& Bucala, 2010).

C: Clinical Trial Registries

Nine clinical trials were identified for this report, none of which directly addresses paediatric-only
PAN treatment, or involve just children. Four trials are RCTs (C1, C3, C8, C9) and five non-
controlled cohort studies (C2, C4, C5, C6, C7).

The RCTs compare:

 corticosteroids and azathioprine versus corticosteroids alone for patients with PAN, CSS and
MPA (age ≥18 years) (C1);
 steroids with/without immunosuppressants for necrotizing vasculitides (age >65 years) (C3);

3
  systemic corticosteroids as first-line therapy with azathioprine or pulse cyclophosphamide
adjunct to treat relapses/failure for PAN and MPA without poor prognosis (age 15-90 years)
(C8);
 methotrexate versus cyclophosphamide for maintaining remission in systemic necrotizing
vasculitides (age 18-80 years) (C9).

The cohort studies examine:

 cyclophosphamide and prednisolone followed by methotrexate to treat vasculitides,
including PAN (age 10-80 years) (C5);
 steroids and methotrexate to treat systemic vasculitis (age 10-80 years) (C6);
 high-dose cyclophosphamide with antithymocyte globulin for systemic necrotizing vasculitis
(age 16-60 years) (C2);
 autologous peripheral blood stem cell transplantation in life-threatening autoimmune
disease including PAN (age 1-55 years) (C7);
 lamivudine for chronic Hepatitis B including patients with PAN (age ≥18 years) (C4).

The results of only one study has been published to date i.e. C8 (Ribi et al., 2010)

Ref Trial Details Study Period

C1 Association Corticosteroid/Azathioprine in Microscopic Polyangiitis/ 2008-2013
Polyarteritis Nodosa or Churg Strauss Syndrome (CHUSPAN2)
Assistance Publique - Hôpitaux de Paris
http://www.clinicaltrials.gov/show/NCT00647166
C2 Hematopoietic Stem Cell Support in Vasculitis 2003-2012
Northwestern University
http://www.clinicaltrials.gov/show/NCT00278512
C3 Treatment of Necrotizing Vasculitides for Patients Older Than 65 Years 2005-2011
(CORTAGE)
Assistance Publique - Hôpitaux de Paris
http://www.clinicaltrials.gov/show/NCT00307671
C4 Lamivudine for Chronic Hepatitis B 1998-2005
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
http://www.clinicaltrials.gov/show/NCT00001457
C5 Cyclophosphamide and Prednisone Followed by Methotrexate To Treat 1995-2004
Vasculitides
National Institute of Allergy and Infectious Diseases (NIAID)
http://www.clinicaltrials.gov/show/NCT00001473
C6 Steroids and Methotrexate to Treat Systemic Vasculitis 1990-2004
National Institute of Allergy and Infectious Diseases (NIAID)
http://www.clinicaltrials.gov/show/NCT00001256
C7 Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life 2000-??
Threatening Autoimmune Diseases
Fairview University Medical Center
http://www.clinicaltrials.gov/show/NCT00006055
C8 CHUSPAN PAN BP Treatment of Polyarteritis Nodosa and Microscopic 1996-??
Polyangiitis Without Poor-Prognosis Factors
Hospices Civils de Lyon
http://www.clinicaltrials.gov/show/NCT00400075

4
C9 Cyclophosphamide Versus Methotrexate for Remission Maintenance in N/K
Systemic Necrotizing Vasculitides
University of Parma
http://www.clinicaltrials.gov/show/NCT00751517

D: Primary Research

Conferences proceedings are only included if a controlled clinical trial was reported.

D.1: Paediatrics
For details of the following studies see Section D.1 of the appendix.

Thirty-one studies report on the pharmacological treatment of children diagnosed with

polyarteritis nodosa. These studies have been subdivided according to study design (in decreasing
strength of evidence).

Randomized controlled trials

A single RCT of 124 patients, aged 15-92 years old, newly diagnosed with either PAN or MPA
explores the effectiveness of corticosteroids in first-line treatment and compares azathioprine and
pulse-cyclophosphamide follow up treatment in the event of corticosteroid failure or relapse. It
concluded that 5-year survival was good and that first-line corticosteroid therapy achieved and
maintained remission in around half the patients, whilst 40% required further immunosuppressant
treatments. Cyclophosphamide and azathioprine were both relatively effective at treating
corticosteroid-resistant disease and major relapse (Ribi et al., 2010).

Non-controlled studies
Three cohort studies examine children with vasculitis: the first, examines 25 cases (11 with PAN)
treated with biologics or multiple sequential biologics. Overall, biologic treatment resulted in
reduced prednisolone requirement, whilst children on sequential biologics treatment showed
improvement with corticosteroid sparing. Infection was a significant consequence occurring in
24% of cases and most severe with infliximab treatment (Eleftheriou et al., 2009). The two
remaining studies differentiate between conditions and thus provide details specific to children
with PAN:
 a national survey in Turkey, revealed all patients with PAN (n = 60) received steroid
treatment, except 3 cases of cutaneous PAN, of children given immunosuppressants 60%
received cyclophosphamide and 10% azathioprine. Lamivudin and interferon were included
in cases of hepatitis B associated PAN. At follow-up there were no fatalities, 3 children
developed end stage renal failure, 16% relapsed, 51.4% remission and 40% treatment free
(Ozen et al., 2007);
 renal involvement in children with PAN (including MPA, n =14) showed varied treatment
regimes: oral and/or pulse steroids with or without oral/intravenous cyclophosphamide. All
children were in remission with the exception of a patient with MPA that developed end-
stage renal disease after 6-year follow up (Cakar et al., 2008)

5
Case studies
Twenty-seven case studies were identified; all report a single paediatric case.

There are seven case reports pertaining to cutaneous PAN (with or without associated conditions).
In each case disease control was achieved, however, treatment regimes varied although the use of
corticosteroids were common to all regimes:
 Corticosteroids only (Thapa, Mallick, Pal, & Ghosh, 2010);
 Corticosteroids with aspirin (Durmaz et al., 2010);
 Corticosteroids with prophylactic penicillin but relapse requiring the use of infliximab (Vega
Gutierrez, Rodriguez Prieto, & Garcia Ruiz, 2007);
 Corticosteroids with biologics (infliximab and rituximab) and methotrexate (Bansal &
Houghton, 2010);
 Corticosteroids with penicillin to treat streptococcus infection (Fleuret et al., 2010)(Marins,
Baptista, Nentzinsky, de Azevedo, & Bica, 2008);
 Corticosteroids and with azathioprine and omeprazole in treating cutaneous PAN following
hepatitis B vaccination (Ventura et al., 2009).

Nine cases of PAN associated with specific conditions were identified, including:
 Three cases involving hypertension responsive to:
o antihypertensives and immunosuppressants (Peco-Antic et al., 2006), although
complications with infective gangrene resulted in amputation of a toe in one case
(Mogale & Shrivastava, 2006);
o antihypertensives, corticosteroids, aspirin, gabapentin and later azathioprine (Wylie
et al., 2006).
 Two cases associated with familial Mediterranean fever, both successfully treated with
colchicine, pulse/oral corticosteroids, cyclophosphamide (Agladioglu et al., 2008) and triple
antibiotic therapy (Ozcakar et al., 2006);
 Two cases associated with Epstein-Barr virus responsive to prednisolone and
cyclophosphamide (Caldeira et al., 2007) and high-dose methylprednisolone, followed by
intravenous pulse cyclophosphamide then immunoglobulin (Park et al., 2007);
 A case associated with hepatitis B, successfully treated with corticosteroids, plasma
exchange and interferon (Belot et al., 2007);
 One case of autoimmune lymphoproliferative syndrome treated with corticosteroids,
cyclophosphamide and allogeneic haemopoietic stem cell transplantation (Naumann-
Bartsch et al., 2010).

A further ten case studies present a variety of successful treatment regimes for polyarteritis
nodosa including:
 Corticosteroids only (Klusmann et al., 2006; Kubota, Koga, & Nakayama, 2007);
 Corticosteroids and cyclophosphamide (Candan et al., 2010; Crankson, Oda, Al-Zaben, Al
Suwairi, & Makanjoula, 2006; Sharma, Kumar, Mishra, & Gaikwad, 2010)
o after non-responsiveness to immunosuppressants and with subsequent treatment
with combination corticosteroids, mycophenolate and infliximab (Wahezi, Gomes,
& Ilowite, 2010)
o relapsing after 6-months, addition of immunoglobulin (1 off dose), intravenous
iloprost and later oral bosentan (Gonzalez-Fernandez & Garcia-Consuegra, 2007)
 Corticosteroid and immunosuppressants (unspecified) (de Carvalho, Pereira, & Shoenfeld,
2008)
 Corticosteroids, cyclophosphamide and azathioprine (Sano et al., 2008);
6
  Corticosteroids and infliximab, following failure with corticosteroids, immunoglobulin and
cyclophosphamide therapies (Brik, Gepstein, Shahar, Goldsher, & Berkovitz, 2007)

One fatality was report in a patient on cyclophosphamide and prednisolone treatment, when
sepsis developed after jejunum resection due to severe bleeding from the small bowel (Kendirli et
al., 2006).

A further five articles could not be accessed to obtain sufficient information to include in this
report. Three concerned with cutaneous polyarteritis nodosa (Kluger, Guillot, & Bessis, 2010;
Russo, 2010; Stringa et al., 2010) and two on systemic PAN (Rogo, Kamat, Arabshahi, & Lateef,
2009) with gastrointestinal involvement (De Carpi et al., 2007).

Two other articles were found which may be of interest:

 Plasma exchange in the treatment of paediatric (Wright, Dillon, & Tullus, 2007);
 Systemic vasculitis presenting with indeterminate intestinal inflammation (Brogan et al.,
2006).

D2: Adults
Similar to the case with paediatric PAN, all primary research papers for adults were uncontrolled
studies (i.e. rank as low-level evidence) comprising 4 cohort studies and 87 case reports (the vast
majority of which were single case reports). Given their low ranking as evidence these are not
detailed in this report, but a reference list of peer-reviewed articles is provided: see Section D.2 of
the Appendix.

E: Overviews and Expert Opinions

These are not detailed in the appendix, as higher-level evidence is available, however, a reference
list of peer-reviewed articles is provided in Section E of the Appendix: this includes articles on
paediatric PAN or vasculitides including PAN, and articles that overview pharmacological
interventions that refer to PAN.

F: Intellectual Property Office

Not relevant to this report

Finally, an article which may be pertinent to this report examines the data held on the Spanish
registry for adverse events of biological therapies in rheumatic diseases (BIOBADASER) (Descalzo
et al., 2007).

CONCLUSION
Primary research studies comprise a majority of the articles included in this report (31/33) with a
further 9 clinical trials ongoing or recently completed and all but one apparently unpublished. A
vast majority of studies (30/31) are uncontrolled study designs i.e. cohort and single-case studies,
that rate as low-level evidence. The single RCT report here includes predominately adults and does
not differentiate cases of PAN and MPA.
7
The primary research describes a diversity of clinical presentations and treatment regimes for
paediatric PAN, further analysis of which is beyond the scope of this report. However, it appears
that in a majority of cases disease control/remission was achieved with oral and/or pulse steroids
with or without oral/intravenous immunosuppressant (mainly cyclophosphamide or azathioprine).
Biologics seem beneficial where cases fail to respond or relapse after steroids and/or
immunosuppressant treatment: but side effects, particularly infections are significant. In children
where PAN presents or is associated with other conditions such as infection, hypertension and
inherited disorders, appropriate therapy is included in the treatment regime. These findings are
consistent with the conclusions of reviews and the evidence summary (for adult vasculitis)
included herein.

In summary, this report identifies the lack of high quality clinical trial evidence as a necessary
research direction in establishing the effectiveness of pharmacological interventions in the
treatment of paediatric polyarteritis nodosa.

ABBREVIATIONS
ANCA Antineutrophil cytoplasmic antibody
BVAS Birmingham Vasculitis Activity Score
CRP C-reactive protein
CSS Churg-Straus syndrome
DMARD Disease modifying anti-rheumatic drug
DNA Deoxyribonucleic acid
ESR Erythrocyte sedimentation rate
HAD-DI Health Assessment Questionnaire – Disease Index
HBV Hepatitis B Virus
HDV Hepatitis D Virus
MPA Microscopic polyangiitis
PAN Polyarteritis nodosa
RA Rheumatoid arthritis
RCT Randomized Controlled Trial
RNA Ribonucleic acid
sd Standard deviation
SF-36 Short Form-36
SLE Systemic Lupus Erythematosus
SNV Systemic necrotizing vasculitis
VDI Vasculitis Damage Index
WG Wegener's granulomatosis

8
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nodosa in a case of familial mediterranean fever.] Gazi Medical Journal, 19(3), 144-146.
Bansal, N., & Houghton, K. M. (2010). Cutaneous polyarteritis nodosa in childhood: A case report
and review of the literature. Arthritis, Article ID 687547, 7 pages.
Belot, A., Ranchin, B., Canterino, I., Trepo, C., Dubourg, L., & Cochat, P. (2007). Hypertensive crisis,
hepatitis B virus and polyarteritis nodosa in a child. Pediatric Nephrology, 22(1), 97-100.
Brik, R., Gepstein, V., Shahar, E., Goldsher, D., & Berkovitz, D. (2007). Tumor necrosis factor
blockade in the management of children with orphan diseases. Clinical Rheumatology, 26(10),
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Brogan, P. A., Malik, M., Shah, N., Kilday, J. P., Ramsay, A., Shah, V., et al. (2006). Systemic
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Cakar, N., Ozcakar, Z. B., Soy, D., Ucar, Y., Fitoz, S., Kara, N., et al. (2008). Renal involvement in
childhood vasculitis. Nephron - Clinical Practice, 108(3), 202-206.
Caldeira, T., Meireles, C., Cunha, F., Valbuena, C., Aparicio, J., & Ribeiro, A. (2007). Systemic
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Candan, C., Civilibal, M., Oktay, G., Canpolat, N., Caliskan, S., Kilicaslan, I., et al. (2010). Classic
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Crankson, S. J., Oda, O., Al-Zaben, A. A., Al Suwairi, W., & Makanjoula, D. (2006). Intestinal
ischamemia in a child due to polyarteritis nodosa: A case report. Tropical Gastroenterology :
Official Journal of the Digestive Diseases Foundation, 27(1), 41-43.
De Carpi, J. M., Castejon, E., Masiques, L., Vilar, P., Anton, J., & Varea, V. (2007). Gastrointestinal
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Nutrition, 44(2), 274-278.
de Carvalho, J. F., Pereira, R. M., & Shoenfeld, Y. (2008). Systemic polyarteritis nodosa following
hepatitis B vaccination. European Journal of Internal Medicine, 19(8), 575-578.
Descalzo, M. A., Montero, D., Erra, A., Marsal, S., Fernandez Castro, M., Mulero, J., et al. (2007).
[Spanish registry for adverse events of biological therapy in rheumatic diseases (BIOBADASER):
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Durmaz, C., Cengiz, N., Baskin, E., Avci, Z., Uslu, Y., & Anarat, A. (2010). [Finger necrosis as initial
manifestation of cutaneous polyarteritis nodosa in a child: Case report]. In Turkish. Turkiye
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Eleftheriou, D., Melo, M., Marks, S. D., Tullus, K., Sills, J., Cleary, G., et al. (2009). Biologic therapy
in primary systemic vasculitis of the young. Rheumatology (Oxford, England), 48(8), 978-986.
Fleuret, C., Kupfer-Bessaguet, I., Prigent, S., Hutin, P., Staroz, F., & Plantin, P. (2010). [Cutaneous
periarteritis nodosa recurring over a period of 30 years in streptococcal infections and
progressing toward systemic vasculitis]. In French. Annales De Dermatologie Et De
Venereologie, 137(3), 220-224.
Gonzalez-Fernandez, M. A., & Garcia-Consuegra, J. (2007). Polyarteritis nodosa resistant to
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Greven, D., Leng, L., & Bucala, R. (2010). Autoimmune diseases: MIF as a therapeutic target. Expert
Opinion on Therapeutic Targets, 14(3), 253-264.

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Kendirli, T., Yuksel, S., Oral, M., Unal, N., Tulunay, M., Dilek, U. S., et al. (2006). Fatal polyarteritis
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Kluger, N., Guillot, B., & Bessis, D. (2010). Ulcerative cutaneous polyarteritis nodosa treated with
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rash and swelling of the limbs after recurrent infections in a teenager: Polyarteritis nodosa.
Acta Paediatrica, International Journal of Paediatrics, 95(10), 1317-1320.
Kubota, Y., Koga, K., & Nakayama, J. (2007). Polyarteritis nodosa cutanea with a varied course.
Nishinihon Journal of Dermatology, 69(5), 505-510.
Marins, K. S., Baptista, R., Nentzinsky, V., de Azevedo, M. N. L., & Bica, B. E. R. G. (2008).
[Cutaneous polyarteritis nodosa in children presenting with digital gangrene and possible
association with group a beta hemolytic streptococcus infection.] In Portuguese. Revista
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Mogale, K. D., & Shrivastava, A. (2006). Childhood polyarteritis nodosa: A clinical diagnosis. Indian
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Peco-Antic, A., Perisic, V., Bonaci-Nikolic, B., Djukic, M., Kruscic, D., & Kostic, M. (2006). Infantile
polyarteritis nodosa presenting as hyponatraemic hypertensive syndrome. Acta Paediatrica,
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Sharma, S., Kumar, S., Mishra, N. K., & Gaikwad, S. B. (2010). Cerebral miliary micro aneurysms in
polyarteritis nodosa: Report of two cases. Neurology India, 58(3), 457-459.
Stringa, M. F., Olivera, A. D., Castro, C., Bonavia, P., Stringa, O. J., Rebora, I., et al. (2010).
[Childhood cutaneous polyarteritis nodosa.] In Spanish. Archivos Argentinos De Pediatria,
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Thapa, R., Mallick, D., Pal, P., & Ghosh, A. (2010). Childhood cutaneous polyarteritis nodosa: An
unusual presentation. Rheumatology International, 30(5), 687-689.
Vega Gutierrez, J., Rodriguez Prieto, M. A., & Garcia Ruiz, J. M. (2007). Successful treatment of
childhood cutaneous polyarteritis nodosa with infliximab. Journal of the European Academy of
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Wahezi, D. M., Gomes, W. A., & Ilowite, N. T. (2010). Cranial nerve involvement with juvenile
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11
 FULL TEXT APPENDIX
SECTION A – GUIDELINES

A1. EULAR recommendations for the management of primary small and medium vessel vasculitis (Mukhtyar et al., 2009). Experts (from 8 European countries and the
USA including 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists, a clinical epidemiologist and a representative from a drug regulatory agency)
identified 10 topics for systematic review using Delphi methodology (modified). Recommendations were made in accordance with the European League Against
Rheumatism’s (EULAR) operating procedures: in the absence of empirical evidence, recommendations were based on consensus opinion. Recommendations for
the management of primary small and medium vessel vasculitis included WG, MPA, CSS, MPA, PAN and essential cryoglobulinemic vasculitis (and excluded
Henoch-Schönlein purpura and Kawasaki disease). Fifteen recommendations were formulated: those most pertinent to the treatment of patients with PAN are:
 Recommendation 1: We recommend that patients with primary small and medium vessel vasculitis be managed in collaboration with, or at centres of
expertise (level of evidence 3, grade of recommendation D);
 Recommendation 6: We recommend a combination of cyclophosphamide (intravenous or oral) and glucocorticoids for remission induction of generalised
primary small and medium vessel vasculitis (level of evidence 1A for WG and MPA, grade of recommendation A; level of evidence 1B for PAN and CSS, grade
of recommendation A);
 Recommendation 8: We recommend the use of high-dose glucocorticoids as an important part of remission induction therapy (level of evidence 3, grade or
recommendation C);
 Recommendation 10: We recommend remission-maintenance therapy with a combination of low-dose glucocorticoid therapy and, either azathioprine,
leflunomide or methotrexate (level of evidence 1B for azathioprine, grade of recommendation A; level of evidence 1B for leflunomide, grade of recommendation
B; level of evidence 2B for methotrexate, grade of recommendation B);
 Recommendation 11: Alternative immunomodulatory therapy choices should be considered for patients who do not achieve remission or relapse on maximal
doses of standard therapy: these patients should be referred to an expert centre for further management and enrolment in clinical trials (level of evidence 3,
grade of recommendation C)
 Recommendation 14: We recommend a combination of antiviral therapy, plasma exchange and glucocorticoids for hepatitis B-associated PAN (level of
evidence 3, grade of recommendation C)
 Recommendation 15: We recommend the investigation of persistent unexplained haematuria in patients with prior exposure to cyclophosphamide (level of
evidence 2B, grade of recommendation C)

Note: level of evidence 1 and grade of recommendation A are highest strength; conversely level of evidence 4 and grade of recommendation D are lowest strength.

12
SECTION B – SYSTEMATIC REVIEWS

Title Sample Methodology/ Summary

Comments

Bansal & Houghton (2010) Case reports and case Computerised search of 582 cases of PAN were identified which included 140 cases of cutaneous PAN: 483 cases
Cutaneous polyarteritis series of paediatric Medline (1950-2009). were excluded.119 cases met inclusion criteria across 51 publications (37 were single case
nodosa in childhood: A (cutaneous) PAN. Restricted to English reports).
case report and review of language articles only. Across all cases skin involvement was present in 96.6% of patients, joint involvement in 58%,
the literature See Section D Exclusion of other muscle involvement in 42.9% and nerve involvement in 18.5%.
reporting on the case identified vasculitis 85.7% of cases tested positive for group A streptococcal infection.
study presented in this including: systemic, Pharmacological therapy included the use of:
paper. infantile and Hepatitis B  corticosteroids in 85.7% of cases;
associated PAN and  DMARDs (including azathioprine, methotrexate, mycophenolate mofetil and
microscopic cyclophosphamide) in 33%;
polyangiitis.  NSAIDs in 10.7%;
 acetylsalicylic acid in 10.7%;
 intravenous immunoglobulin in 9.8%;
 biologics (etanercept and infliximab) 1.8% and
 other (including adrenocorticotropic hormone, colchincine, dapsone, oxpentifylline and
platonin) in 10.7%.
Concludes that the majority of children respond well to corticosteroid therapy, but some need
DMARDs and biologics.
Highlights the need for multicentre paediatric vasculitis disease registries to inform the
development of standardized best clinical practice for children with cutaneous PAN.

13
Phillip & Luqmani (2008).
Mortality in systemic
vasculitis: A systematic
review.
Peer-reviewed articles Computerised search of For PAN only
which pertain to Sheffield Hallam Reported survival rates are around 75-80%, increasing for hepatitis B-related PAN to 83% (at
mortality and vasculitis University LitSearch 5-years).
including: PAN, WG, website (2008) and Most deaths are due to active vasculitis.
MPA, CSS, Henoch- Medline from 1950 to In patients with an initial 5-factor score ≥ 2 cyclophosphamide treatment improves survival.
Schönlein, Kawasaki April 2008. Whilst gastrointestinal involvement has been associated with poor prognosis, aggressive
disease, giant cell Restricted to English medical treatment and improved surgical management has resulted in improved survival rates
Arteritis and Takayasu language articles only. to 77% for acute abdomen and 91% for other gastrointestinal involvement.
Arteritis. Hepatitis B-related PAN is significantly affected by anti-viral treatment as part of a treatment
regime including glucocorticosteroids and plasma exchange.
Significant predictors of mortality include: increasing age, CNS, cardiac or gastrointestinal
involvement, cardiomyopathy and proteinuria.
Fatal complications from treatment regimes are significant including immunosuppression
related sepsis and cyclophosphamide related bladder cancer.
Concludes that improved management has resulted in decreased mortality, with treatment for
hepatitis B-related PAN potentially enabling cure.

SECTION C – CLINICAL TRIAL REGISTRIES

Title Sponsors and Status Summary

C1 Association Corticosteroid/
Azathioprine in Microscopic
Polyangiitis/ Polyarteritis Nodosa or
Churg Strauss Syndrome
(CHUSPAN2)
http://www.clinicaltrials.gov/show/N
CT00647166
Assistance Publique - Hôpitaux de RCT (placebo control, n = 104) to determine if corticosteroids plus azathioprine results in
Paris greater remission rates and lower relapse rates without increasing adverse events in patients
newly-diagnosed with PAN, MPA or CSS, compared to corticosteroids alone.
2008-2013
Patients: 18 years and older, newly diagnosed (within 15 days) with PAN, MPA or CSS and
Ongoing
with no Factor of Poor Prognosis.
Outcomes include: combined rate of remission treatment failure and relapse at 24 months,
initial remission rate, rates and severity of adverse events, number of deaths
Time-points: 24-months

14
C2 Hematopoietic Stem Cell Support in Northwestern University Cohort study (n = 10) to determine effectiveness of high dose cyclophosphamide with anti-
Vasculitis thymocyte globulin (ATG) for patients with SNV.
2003-2012
http://www.clinicaltrials.gov/show/N Patients: 16-60 years old with diagnosis of SNV (Refractory Vasculitis, Necrotizing Vasculitis,
Ongoing
CT00278512 Neurovascular Behcet's Disease, and Sjogren's Syndrome)
Outcomes: Survival; Change in Birmingham Vasculitis Activity Score and Change in Vasculitis
Damage Index.
Time-points: baseline, 5-years.
C3 Treatment of Necrotizing Assistance Publique - Hôpitaux de RCT (active control, n = 108) to compare the morbidity associated with two treatment regimes
Vasculitides for Patients Older Than Paris (steroids with and without immunosuppressants) for necrotizing vasculitides in patients over 65
65 Years (CORTAGE) years old.
2005-2011
http://www.clinicaltrials.gov/show/N Patients:65 years and older, newly diagnosed with WG, MPA, PAN (without HBV infection), or
Ongoing
CT00307671 CSS
Outcomes: Number of side effects, survival, remission rate, relapse rate, BVAS, VDI, HAQ-DI,
SF-36
Time-points: baseline, 3 years.
C4 Lamivudine for Chronic Hepatitis B National Institute of Diabetes and Cohort study (n = 60) to determine the safety, antiviral activity and clinical effectiveness of
Digestive and Kidney Diseases lamivudine in patient with chronic Hepatitis B.
http://www.clinicaltrials.gov/show/N
(NIDDK)
CT00001457 Patients: 18 years or older with diagnosis of Hepatitis B including atypical serology (HBeAg
1998-2005 negative); extra-hepatic manifestations (Polyarteritis nodosa); chronic delta hepatitis; and
typical HBeAg- positive chronic hepatitis B.
Completed
Outcomes include: changes in HBV DNA and HDV RNA, viral markers, levels of
aminotransferases and liver histology.
Time-points: baseline, 1 year, 5 years.
C5 Cyclophosphamide and Prednisone National Institute of Allergy and Cohort study (n = 100) to evaluate the safety and effectiveness of a staged approach using
Followed by Methotrexate To Treat Infectious Diseases (NIAID) prednisone plus cyclophosphamide followed by methotrexate in treating vasculitides.
Vasculitides
1995-2004 Patients: 10-80 years old diagnosed with WG, PAN or a related systemic vasculitis.
http://www.clinicaltrials.gov/show/N
Completed Outcomes include: time to disease remission, rate and time of relapse, incidence of drug-
CT00001473
related adverse effects.
Time-points: baseline, at months 1, 2, 6, 9, 12, 18, 21, 24, 27, 33, 39, 45 and 51.

15
C6 Steroids and Methotrexate to Treat National Institute of Allergy and
Systemic Vasculitis Infectious Diseases (NIAID)
http://www.clinicaltrials.gov/show/N 1990-2004
CT00001256
Completed
C7 Autologous Peripheral Blood Stem
Cell Transplantation in Patients
With Life Threatening Autoimmune
Diseases
http://www.clinicaltrials.gov/show/N
CT00006055
C8 CHUSPAN PAN BP Treatment of
Polyarteritis Nodosa and
Microscopic Polyangiitis Without
Poor-Prognosis Factors
http://www.clinicaltrials.gov/show/N
CT00400075
See Ribi et al (2010) in section D
C9 Cyclophosphamide Versus
Methotrexate for Remission
Maintenance in Systemic
Necrotizing Vasculitides
http://www.clinicaltrials.gov/show/N
CT00751517
Fairview University Medical Center
2000-??
Ongoing (in 2005 at last update)
Hospices Civils de Lyon
1996-??
Complete
University of Parma
N/K (ongoing in 2008 at last update)
Cohort study (n = 100) to evaluate the safety and effectiveness of prednisone and
methotrexate in treating systemic vasculitis.
Patients: 10-80 years old diagnosed with active Wegener's granulomatosis, polyarteritis
nodosa, Churg-Strauss vasculitis, or microscopic polyangiitis overlap, or with
glomerulonephritis and a positive blood test for C-ANCA; or inflammatory sinusitis or lung
nodule or infiltrates in the absence of infection.
Outcomes include: FBC, liver-function tests, blood chemistry, kidney function tests, lung
function tests.
Time points: base-line, various timepoints depending on indication over 2.5-3 years.
Cohort study (n = 10) to investigate the effectiveness of autologous peripheral blood stem cell
transplant in patients with life-threatening autoimmune disease.
Patients: 1-55 years old diagnosed with life-threatening autoimmune disease including WG,
PAN, CSS, SLE, RA and Takayasu Arteritis.
Outcomes: clinical and laboratory parameters (not specified)
RCT (active control, n = 124) to determine the efficacy of systemic corticosteroids as first-line
treatment of PAN and MPA without poor-prognosis factor, and to compare the safety and
efficacy of azathioprine versus pulse cyclophosphamide as adjuncts to treat failure or relapse.
Patients: 15-90 years old diagnosed with PAN or MPA without poor prognosis factor
Outcomes: disease-free survival rate defined by number of events at study end and overall
survival, relapse rate and adverse events at end of study.
Time-points: baseline and 5 years
RCT (active control) to compare the efficacy of Methotrexate versus Cyclophosphamide for
maintaining remission in SNV.
Patients: 18-80 years old diagnosed with clinically active WG, CSS, PAN or MPA.
Outcomes: Time from remission to relapse, Recurrence rate, Therapy-related toxicity,
Hospitalization rate and Mortality
16
SECTION D.1 – PRIMARY RESEARCH: PAEDIATRIC
Square brackets around the title of an article indicate that whilst the article’s abstract is available in English, the main body of the article is NOT in English.

Title Sample Methodology/Com Summary

ments
Agladioglu, Ezgu, Peru, Case report. To describe Familial Mediterranean fever was detected and treated with colchicine. Symptoms persisted
Fidan, Onal, Hasanoglu 9-year-old boy presenting presentation, and further clinical investigation including angiography revealed hepatic artery aneurysms: PAN
& Buyan (2008). with abdominal pain and treatment and was suspected. A treatment regime of:
Polyarteritis nodosa in fever. outcomes.  Pulse Methylprednisolone and pulse cyclophosphamide in addition to the colchicine
a case of familial was implemented.
Mediterranean fever. The patient responded well.
Bansal & Houghton Case report. To describe Clinical examination and investigation showed febrility, leukocytosis with neutrophilia, elevated
(2010) Cutaneous 7½-year-old girl presenting presentation, ESR and CRP and mild thickening of prevertebral soft tissue. A diagnosis of cervical adenitis
polyarteritis nodosa in with massive cervical treatment and was made and the girl was admitted for
childhood: A case oedema unresponsive to outcomes.  Antibiotic therapy
report and review of the erythromycin prescribed for
literature pharyngitis and fever. The patient deteriorated eventually developing subcutaneous nodules, Myositis, arthritis, livedo
reticularis and mononeuritis multiplex.
See Section B reporting on  Corticosteroid treatment showed initial improvement in the condition, however,
the evidence review section relapses required the use of DMARDs and biologic therapy (including methotrexate,
of this paper. infliximab and rituximab)
The girl responded well rituximab and tolerated weaning of prednisolone.
Belot, Ranchin, Case report. To describe Previous medical history revealed “postinfectious acute nephritis” at 2 years of age and mild
Canterino, Trepo, presentation, hepatitis. Clinical examination and investigations showed significant liver and spleen
4-year-old Turkish boy
Dubourg & Cochat treatment and enlargement, peripheral neuropathy with muscular atrophy and retinopathy. ESR, white blood
presenting with poor general
(2007). Hypertensive outcomes. cell and platelet counts were elevated, also proteinuria with reduced glomerular filtration rate:
condition, weariness,
crisis, hepatitis B virus this led to a diagnosis of PAN. There was also presence of HBV antigen.
anorexia, fever, abdominal
and polyarteritis nodosa Emergency antihypertensive treatment was given:
pain, arthralgias and severe
in a child.  combined intravenous nicardipine, propranolol and furosemide given for a week,
hypertension.
followed by ACE-inhibitors: hypertension was controlled after a month.
PAN treatment regime:
 sequential protocol used in adults with HVB-associated PAN including: corticosteroids,
plasma exchange and Interferon: which was well tolerated by the patient
Nine years later, there were no signs of PAN, and blood pressure, GFR and ESR were normal:
the patient had been treatment free for 7 years.

17
Brik, Gepstein, Shahar, Case report. To describe At first presentation physical examination revealed febrility, paresis of the right oculomotor
Goldsher & Berkovitz presentation, nerve with slight pyramidal weakness of his left side, An initial diagnosis of postinfectious
3 children with rare vascular
(2007). Tumor necrosis treatment and autoimmune demyelinative disease was made and the patient treated with:
conditions treated with
factor blockade in the outcomes.  high dose methylprednisolone for 5 days with little improvement, so a course of intravenous
infliximab: PAN (n = 1); -1
management of immunoglobulin (2 g.kg ) was added.
sarcoidosis (n = 1) and
children with orphan Whilst the patient initially improved the patient deteriorated showing a range of symptoms
familial Mediterranean
diseases. including muscle and abdominal pain, a linear nodular rash on both legs and livedo reticularis
Fever (n =1). coupled with a skin lesion biopsy a diagnosis of PAN was made and a treatment regime
implemented:
 high-dose methylprednisolone continued with little improvement after a month, so
PAN only: intravenous cyclophosphamide was added.
However, neurological deterioration continued with a MRI scan revealing bilateral symmetric
3½-year-old boy who had
thalamic infarcts, 2 large vascular aneurysms, and evidence of cerebral atrophy.
first presented at 20-months
of age with strabismus,  A therapeutic trial with infliximab was agreed: significant clinical improvement was seen
following the first dose.
ataxia and behavioural
changes after a short febrile Over the subsequent 10 months of infliximab treatment (6 doses) the dosage of corticosteroids
illness. was successfully tapered off with continued clinical improvement.
3 years after finishing the infliximab treatment regime, the child remains well and without
evidence of disease activity: there is residual damage expressed with weakness of the right
oculomotor nerve.
Cakar, Ozcakar, Soy, Cohort study. To explore the For PAN only:
Ucar, Fitoz, Kara, demographic,
152 of 816 children under Kidney involvement was seen in 14 or 31 patients (45%): 9 patients had childhood PAN and 5
Uncu, Atakan, Ekim & clinical, laboratory
the age of 17 years with a MPA.
Yalcinkaya (2008). features and
diagnosis of Henoch- On presentation: 11 patients (79%) showed haematuria; 8 patients (57%) had proteinuria (1
Renal involvement in treatment modalities
Schönlein purpura (n = 132), had nephrotic syndrome); 7 patients (50%) were hypertensive. 2 patients had known familial
childhood vasculitis. of patients with
PAN (n = 14), Takayasu Mediterranean fever.
vasculitis with renal
Arteritis (n = 3) or Wegener In the 5 cases of MPA renal biopsy was undertaken: 4 showed focal segmental crescentic
involvement.
Granulomatosis (n = 1) with glomerulonephritis and 1 had necrotizing vasculitis.
renal involvement.
Treatment regimes varied and included the following combinations:
For PAN only: For PAN only:  Oral and pulse steroids (n = 2)
Female n=8, male n=6; Mean follow up:  Oral prednisone and intravenous cyclophosphamide (n = 1)
72.08 ± 36.37 (sd;  Oral prednisone, pulse steroids and oral cyclophosphamide (n = 5)
Age at diagnosis: 10.88 ±
range 4-112) months  Oral prednisone, pulse steroids and intravenous cyclophosphamide (n = 6).
3.23 (sd; range 4-16) years At follow up all patients, except one, were in remission. A patient with MPA developed end-
stage renal disease after 6 years follow-up.

18
Caldeira, Meireles, Case report. To describe Clinical examination and investigation revealed extensive cranial haemorrhage, fibroid necrosis
Cunha, Valbuena, 8-year-old boy presenting presentation, lesions in the kidneys, renal aneurysms and the presence of Epstein-Barr virus. Diagnosis was
Aparicio, & Ribeiro with fever, shock, renal treatment and systemic PAN with associated Epstein-Barr virus.
(2007). Systemic failure, hypertension and outcomes. Treatment was begun including:
polyarteritis nodosa sudden deterioration in  prednisolone (2 mg.kg .day ) and intravenous pulse of cyclophosphamide
-1 -1

associated with acute consciousness. The patient responded well and after 1 months treatment was discharged on:
Epstein-Barr virus  Monthly intravenous pulses of cyclophosphamide, oral prednisolone and antihypertensive
infection. drugs (with continued rehabilitation).
Candan, Civilibal, Oktay, Case report. To describe On admission given sodium nitroprusside infusion (for hypertension) and later oral nifedipin and
Canpolat, Caliskan, presentation, alphamethyldopa.
14-year-old girl presenting
Kilicaslan, Sever, treatment and
with recent onset (within 24 Clinical examination and investigations lead to a diagnosis of classical PAN, resulting in the
Kasapcopur & Arisoy outcomes.
h) hypertension and following treatment protocol:
(2001) Classic
 Intravenous pulse methylprednisolone therapy (30 mg.kg .day , max.1 g) for 5
-1 -1
developing anuria.
polyarteritis nodosa
presenting with acute consecutive days;
 followed by intravenous cyclophosphamide pulse therapy (750 mg/m ) for 1 day;
2
anuric renal failure.
 then oral prednisone (2 mg.kg .day , max. 60 mg) and gradually tapered after 4 weeks.
-1 -1

Renal function total recovered and hemodialysis was discontinued 3 weeks post-treatment and
she was discharged 1 month after admission in good general health. Maintenance therapy
was:
 Prednisolone (10mg on alternate days)
 Cyclophosphamide intravenous pulse (monthly)
 Enalapril and nifedipin (hypertension): discontinued at follow up.
At 3-year follow up, patient remained in remission (normal renal function tests; proteinuria 96
-1
mg.day ).

Crankson, Oda, Al- Case report.
Zaben, Al Suwairi & 10-year-old boy referred
Makanjoula (2006). after an appendectomy with
Intestinal ischamemia fever, vomiting, diarrhoea,
in a child due to abdominal pain, weight loss,
joint pain and skin rash.
polyarteritis nodosa: a
case report.
De Carvalho, Pereira & Case report
Shoenfeld (2008). 14-year-old boy presenting
Systemic polyarteritis with livedo reticularis, fever,
nodosa following weight loss, testicular pan
hepatitis B vaccination. and paresthesias, 2 months
after receiving a third dose
of Hepatitis B vaccine.
To describe Shortly following admission peritonitis developed and an emergency laparotomy revealed
presentation, ischemia of the jejunum which needed partial resection. Histological examination revealed
treatment and features consistent with PAN and consequently treatment was initiated with:
outcomes.  Steroids and cyclophosphamide.
After 19 months the patient is asymptomatic and in good health.
To describe Clinical examination and investigation including inflammatory markers revealing high ESR and
presentation, CRP, led to a diagnosis of PAN.
treatment and
Treatment with corticosteroids and immunosuppressant led to the condition improving.
outcomes.
Concluded that after reviewing the literature, which showed 27 cases of vasculitis following
Hepatitis B vaccination, that vaccination may be the trigger factor for vasculitis in individuals
with genetic predisposition.

19
Durmaz, Cengiz, Baskin, Case report. To describe Treatment commenced with heparin infusion due to elevated ESR and CRP. Further
Avci, Uslu & Anarat 10-year-old girl presenting presentation, investigation lead to a diagnosis of cutaneous PAN: heparin was discontinued and intravenous
(2010) [Finger necrosis with bilateral necrotic lesions treatment and pulse methylprednisolone therapy started.
as initial manifestation affecting the toes. outcomes.
At discharge skin lesions showed marked improvement and the patient continued on a
of cutaneous treatment regime of oral prednisone and aspirin.
polyarteritis nodosa in a
child: Case report]. In
Turkish.
Eleftheriou, Melo, Marks, Cohort study. To describe biologic Overall there was a significant reduction in BVAS (median 8.5 (range 5-32) to 4 (range 0-19; p
-
Tullus, Sills, Cleary, 25 patients (11 male) with treatment regimes = 0.003) and median daily prednisolone requirement (1 (range 0.2-2) to 0.25 (range 0-1) mg.kg
1 -1
Dolezalova, Ozen, active primary systemic and examine their .day ; p < 0.001) between initiation of therapy and follow up at 32 months (median).
Pilkington, Woo, Klein, vasculitis (ANCA-positive n efficacy and safety in
Patients receiving multiple sequential biologics exhibited a clinical improvement with
Dillon & Brogan (2009). =6; PAN n = 11; Behcet’s children with primary
corticosteroid sparing.
Biologic therapy in disease n = 1; unclassified systemic vasculitis.
primary systemic vasculitis n = 7) and treated Primary outcome 24% of patients showed infection, with patients on infliximab showing the most severe infection.
vasculitis of the young. with biologic agents measures include:
(infliximab n = 7; rituximab n The study highlighted the need for further multicentre standardization of therapeutic regimes
daily corticosteroid
=6; etanercept n = 4; dose, BVAS and and data collection to inform clinical trials of biologics in paediatric systemic vasculitis.
adalimumab n = 1; or adverse events
multiple sequential biologics (including infection
n = 7. rates).
Median age 8.8 (range 2.4-
16) years.
Fleuret, Kupfer- Case report. To describe Patient history revealed recurring episodes of myaglia, arthalgia and inflammatory
Bessaguet, Prigent, 35-year-old man presenting presentation, subcutaneous nodules since 5-years of age: which appeared to be precipitated by
Hutin, Staroz & Plantin with retropharyngeal treatment and streptococcal infection.
(2010). [Cutaneous abscess associated with outcomes.
Treatment with combined oral corticosteroids and treatment for acute infection led to
periarteritis nodosa fever, myalgia, arthalgia and
improvement for each episode.
recurring over a period inflammatory subcutanenous
of 30 years in nodules. Diagnosed with Concluded that post-streptococcal cutaneous PAN may slowly progress to systemic
streptococcal infections cutaneous PAN at 10-years involvement.
and progressing toward of age.
systemic vasculitis]. In
French.

20
Gonzalez-Fernandez & Case report. To describe Initial treatment was
Garcia-Consuegra presentation,  High-doses of corticosteroid and cyclophosphamide
3-year-old girl diagnosed
(2007). Polyarteritis treatment and During which her condition resolve. However she relapsed after 6-months and was admitted to
with PAN referred from
nodosa resistant to outcomes. hospital during which some cutaneous lesions developed into digital necrosis. She was placed
another region.
conventional treatment on the conventional regime (as above?) with the addition of:
 a single dose of intravenous immunoglobulin (2 g.kg )
-1
in a pediatric patient.
 intravenous iloprost 2 ng.kg .min over 6 hours for 5 days
-1 -1

and after 4 weeks

 oral bosentan for 12 weeks
There was gradual improvement with her fingers and at discharge she was given a treatment
regime of:
 gradually tapered doses of oral corticosteroids, bosentan, and monthly pulsed injections of
cyclophosphamide.
6 months after discharge the cutaneous lesions, including digital necrosis had totally resolved.
Full article was not accessible to clarify details

Kendirli, Yuksel, Oral, Case report. To describe Clinical investigation revealed multiple aneurysms of the hepatic and superior mesenteric
Unal, Tulunay, Dilek & 15-year-old boy with PAN presentation, arteries. Treatment was initiated with:
Yalcinkaya (2006). and gastrointestinal treatment and  cyclophosphamide and prednisolone
Fatal polyarteritis involvement. outcomes.
this resulted in a decrease in size of the aneurysms and progression of symptoms with severe
nodosa with bleeding from the small bowel: resection of the jejunum was performed. However, the patient
gastrointestinal developed sepsis and died.
involvement in a child.

Full article was not accessible to clarify details

Klusmann, Megahed, Case report.
Kruse, Schneider, 17-year-old girl presenting
Schmidt & Niehues with history of recurrent
(2006). Painful rash upper respiratory tract
infections and conjunctivitis,
and swelling of the
limbs after recurrent with subsequent
infections in a teenager: development of a painful
Polyarteritis nodosa. erythema nodosum-like rash
on upper and lower
extremities.
To describe Clinical examination and investigation including skin biopsy confirmed a diagnosis of PAN.
presentation, Initially treated with
treatment and  intravenous immunoglobulins
outcomes.
this failed but
 systemic steroids
resulted in rapid improvement in the condition.

21
Kubota, Koga & Case-report. To describe Clinical examination and investigations revealed thrombus in vessels of the feet and
Nakayama (2007). 17-year-old student presentation, antinuclear antibodies this led to a diagnosis of livedoid vasculopathy.
Polyarteritis nodosa presenting with dark purpuric treatment and The patient later developed purpura and swelling bilaterally in the lower legs and feet with
cutanea with a varied macules bilaterally on the outcomes. neuropathy: biopsy showed necrotizing vasculitis in vessels of the dermis into the
course. lower leg and petechiae of subcutaneous fat. A diagnosis of vasculitis allergic cutis (Ruiter) and PAN was made and the
the feet. patient received treatment including:
 oral steroid
the patient responded well, but with tapering of the steroid some nodules reappeared which on
examination showed necrotizing vasculitis in the arterioles of subcutaneous fat again leading to
a diagnosis of PAN.
 oral steroids were continued for 2 months with good result.
Marins Baptista, Case report To describe A diagnosis of cutaneous PAN was made based on clinical investigation: this was associated
Nentzinsky, de 9-year-old child presenting presentation, with Group A β-haemolytic streptococcus infection.
Azevedo & Bica (2008). with subcutaneous nodules treatment and
A treatment regime of prednisolone and Bencilpenicilina Benzatina was implemented.
[Cutaneous polyarteritis and ischaemic changes to outcomes.
nodosa in children the fingertips.
presenting with digital Full article in Portuguese and therefore further details were not available
gangrene and possible
association with group
a beta hemolytic
streptococcus
infection.] In
Portuguese
Mogale & Shrivastava Case report. To describe Clinical examination and investigation including elevated inflammatory parameters, led to a
(2006). Childhood 6-year-old boy presenting presentation, diagnosis of PAN. Treatment included:
polyarteritis nodosa: A with dry gangrene of fingers treatment and  immunosuppressants and antihypertensives
clinical diagnosis. and toes and hypertension. outcomes.
along with toe amputation due to infected gangrene. This result in clinical improvement in the
child’s condition.

22
Naumann-Bartsch, Case report To describe Following initial diagnosis treatment to control lymphoproliferation, Coombs-positive haemolytic
Stachel, Morhart, 15-month-old boy diagnosed presentation, anaemia, neutropenia and autoimmune thrombocytopenia was initiated involving:
Staatz, Jungert, with autoimmune treatment and  Repeated high-dose pulses of Methylprednisolone, intravenous immunoglobulin and
Schwarz & Holter lymphoproliferative outcomes. mycophenolate mofetil.
(2010). Childhood syndrome.
At 3-years of age the disease exacerbated with weakness, peripheral facial palsy, total body
polyarteritis nodosa in pain and painful subcutaneous nodules on the fingertips, treatment involved:
autoimmune
lymphoproliferative  High-dose Methylprednisolone course.
syndrome. Resulting in the condition (including neurological and dermatological symptoms) improving.
3 months later the boy presented with progressive lymphadenopathy and splenomegaly,
abdominal pain, arterial hypertension, thoracic maculopapular dark-red skin lesions and right
arm paresis. Further clinical investigations which included finding multiple arterial aneurysms
resulted a diagnosis of PAN: and a treatment protocol was initiated involving:
 Cyclophosphamide pulse therapy (0.5 g/m per course)
2

However, disease control was not achieved after several courses: new aneurysms appeared
and others progressed. Therefore:
 Allogeneic haemopoietic stem cell transplantation (HSCT) was undertaken: successful on
rd
the 3 attempt (after conditioning with thiotepa, alemtuzumab, fludarabine and total body
irradiation).
This resulted in regression of lymphadenopathy, hepatosplenomegaly and aneurysms with
improvement of neuropathy. Maintenance therapy involved only:
 Low-dose antihypertensive medication
12-months post HSCT complete donor chimerism was observed and the patient remains in
good clinical condition.
Ozcakar, Yalcinkaya, Case report. To describe An initial diagnosis of familial Mediterranean fever and infection was made and was treated
Fitoz, Yuksel, Acar, A 15-year-old boy presenting presentation, with
Caltik & Ekim (2006). with fever, lack of appetite, treatment and  Colchicine and triple antibiotic therapy
Polyarteritis nodosa: weight loss, weakness, outcomes.
myalgia, and loss of and was referred to a second hospital for investigation: clinical, laboratory and ultrasound
Successful diagnostic findings (including cystic aneurysms) which confirmed a diagnosis of PAN.
imaging utilizing pulsed sensation in the right hand
and color Doppler following appendectomy 25-  Pulse methylprednisolon for 6 days
ultrasonography and days previous. followed by
computed tomography  Oral steroid and cyclophosphamide
angiography. patient showed clinical improvement after 10 days, and in the first month of therapy almost total
disappearance of aneurysms was noted.

23
Ozen, Bakkaloglu, Cohort study. To characterise For PAN only
Dusunsel, childhood
National questionnaire 60 patients were identified (5.6% of vasculitides reported) of which 51% were male. Mean age
Soylemezoglu, Ozaltin, vasculitides in
survey of 15 referral centres was 14.45 ± 5.50 (range 13-18) years. 3 patients had known familial Mediterranean fever.
Poyrazoglu, Turkey and to
in Turkey.
Kasapcopur, Ozkaya, establish a national Organ involvement included: gastrointestinal (33.3%), central nervous system (20%), kidney
Yalcinkaya, Balat, Vasculitides included: registry. disease (53%) and skin (59.3%). 57.6% patients had myalgia and/or arthritis.
Kural, Donmez, Alpay, Henoch-Schönlein purpura;
Time frame: Acute phase reactants were elevated in all patients (ESR and CRP), except 4 with cutaneous
Anarat, Mir, Gur- childhood PAN, Takayasu
Henoch-Schönlein PAN. Whilst 91.7% patients showed elevated and antistreptolysin-O.
Guven, Sonmez & Gok Arteritis, Kawasaki disease,
purpura reported in
(2007). Childhood Wegener’s Granulomatosis, Further classification was possible for 40 patients: 47.5% had systemic PAN; 25% microscopic
the previous year;
vasculitides in Turkey: Churg-Strauss syndrome PAN; 15% cutaneous PAN; and 12.5% classic PAN associated with Hepatitis B antigen.
other vasculitides
A nationwide survey. and Behcet disease.
reported over 5- Treatment:
years.  With the exception of 3 patients with cutaneous PAN all received steroids.
Median patient  Cyclophosphamide (59.5% of patients) was the most commonly prescribed
follow up 66 (range 1 immunosuppressant for classic, microscopic and systemic pain. 10% patients received
- 44) months azathioprine.
 Lamivudin or interferon treatment was used for classic PAN associated with Hepatitis B
virus.
Outcome at follow up:
 No fatalities
 3 patients progressed to end-stage renal failure: 1 had a successful renal transplant.
 16% patients had a relapse
 51.4% patients in remission
 40% off treatment at time of follow up

24
Park, Choi, Kim, Ye, Park Case report. To describe Physical examination and investigations revealed an erythematous rash on the upper
& Suh (2007). presentation, extremities, trunk and face, 2 palpable nontender lymph nodes on the left side of the neck and
5 year-old boy presenting
Successful treatment of treatment and a tender abdomen. Many blood parameters were abnormal including elevated platelet count,
with malaise, fever,
pediatric systemic outcomes. aspartate aminotransferase, total and direct bilirubin, alkaline phosphate, gamma
abdominal pain, myalgia and
polyarteritis nodosa glutamyltransferase and amylase. Epstein-Barr virus antigen IgG was present. Erythema
erythematosus rash after
with cholestatic multiforme was revealed on biopsy.
taking a cold remedy.
hepatitis.
At 15 days post-admission melena and severe abdominal pain developed and on further
investigation multiple microaneurysms in the hepatic, renal and superior mesenteric arteries
were identified. A diagnosis of systemic PAN was made and treatment began on day 23 with:
 Intravenous methylprednisolone (2 mg.kg .day )
-1 -1

There was no significant improvement and after 4 days:

 Pulse methylprednisolone (25 mg.kg .day ) was given for 5 days.
-1 -1

Abdominal pain continued and liver function tests were still abnormal.
 Intravenous pulse cyclophosphamide (500mg.day ) then immunoglobulin was
-1

administered. A second pulse of cyclophosphamide was given at day 59 and prednisolone

-1
dosage tapered up to 30 mg.day .
Clinical picture improved gradually, liver function tests normalized and prednisolone dosage
-1
tapered to 10 mg.day during the 7 months following discharge.
Peco-Antic, Perisic, Case report. To describe Clinical investigation revealed small renal arterial aneurysms, arterial cut-off, arterial tapering
Bonaci-Nikolic, Djukic, 17-month-old gild presenting presentation, stenosis and perfusion defects: a diagnosis of classical PAN was made. Treatment included
Kruscic & Kostic with severe hypokalaemia, treatment and  Immunosuppressant therapy and antihypertensives
(2006). Infantile hypoatraemic dehydration, outcomes.
polyuria, proteinuria after 4 months PAN was well controlled and hypoatraemic hypertensive syndrome resolved.
polyarteritis nodosa
presenting as associated with arterial
hyponatraemic hypertension and systemtic
hypertensive syndrome. inflammatory disease.

25
Ribi, Cohen, Pagnoux, RCT To determine the 26 patients (21%) failed to respond to initial corticosteroid treatment. For the remaining 98
Mahr, Arene, Puechal, 124 patients (72 men, 52 efficacy of systemic patients corticosteroid treatment resulted in disease remission: of which 2 became
-1
Carli, Kyndt, Le Hello, women) newly diagnosed corticosteroids as corticosteroid dependent (prednisone could not be decreased below 20mg.day ) and 46
st
Letellier, Cordier & with PAN (n =58) or MPA (n 1 -line treatment. To experienced relapse requiring immunosuppressant medication.
Guillevin (2010) = 66) without poor compare safety and
Of the 74 patients who experience corticosteroid failure or relapse: 9 (12%) developed severe
Treatment of prognostic factors and efficacy of
vasculitis. 50 patients (40%) attained sustained disease remission. 49 (40%) of patients were
polyarteritis nodosa and treated with corticosteroids. azathioprine vs nd
prescribed 2 -line immunosuppressants.
microscopic polyangiitis If treatment failed or disease pulse cyclo-
without poor-prognosis relapsed patients were phosphamide as 39 of the 56 patients who did not respond to corticosteroids alone were randomized (PAN = 13;
factors a prospective randomised to receive 6- adjunct in patients MPA = 26) to receive azathioprine or cyclophosphamide treatment. Remission was achieved in
randomized study of months therapy with who experience 14 or 20 receiving azathioprine and 13 of 19 receiving cyclophosphamide pulses, 2 and 6
one hundred twenty- azathioprine or 6 pulses of treatment failure or deaths occurred across the treatment groups respectively. Note: youngest person randomized
four patients. cyclophosphamide. relapse. was 23 years old.
st
Mean age: Concluded that for patients with PAN or MPA overall 5-year survival is good, although 1 -line
See C8 in Section C 56.5±16.6 (sd; range corticosteroid therapy achieved and maintained remission in approximately half of patient,
15.7–92) years whilst 40% of patients required further immunosuppressant therapy. Both azathioprine and
pulse-cyclophosphamide are relatively effective in cases of major relapse and corticosteroid
Mean follow up: 62 ±
resistant disease.
33 (sd; range 3-135)
months.
Outcomes: time to
events: treatment
failure, minor and
major relapses
and/or death,
[disease-free]
survival rate.

26
Sano, Miyamae, Case report. To describe Clinical examination and investigations revealed elevated levels of CRP and ESR, multiple
Nakagishi, Kinoshita, 14-year-old boy presenting presentation, colorectal ulcerations, bilateral renal infarction and renal artery microaneurysms: leading to a
Ozawa, Imagawa, Mori, with fever, abdominal pain, treatment and diagnosis of PAN.
Asayama & Yokota weight loss, and watery and outcomes. The boy was treated with a 12-month course of intravenous pulse cyclophosphamide and
(2008). bloody diarrhoea.
prednisolone/azathioprine therapy, this resulted in total disappearance of inflammatory
[Gastrointestinal indicators, renal infarction and microaneurysms.
involvement and renal
infarction in a boy with
classic polyarteritis
nodosa diagnosed with
3D-computed
tomography
angiography]. In
Japanese
Sharma, Kumar, Mishra Case report. To describe In both patients clinical investigations revealed cerebral haematomas and dispersed
& Gaikwad (2010). Two patients: 13-year-old presentation, aneurysms together with serological findings both patients were diagnosed with PAN.
Cerebral miliary micro boy and 32-year-old man treatment and Both patients responded well to steroids and cyclophosphamide treatment (no long term
aneurysms in presenting with seizure outcomes. outcomes were reported).
polyarteritis nodosa: followed by
Report of two cases. unconsciousness and
sudden onset left flank pain.
Thapa, Mallick, Pal & Case report. To describe Clinical examination revealed some digital resorption of the terminal phalanges of the hands
Ghosh (2010). 6-year-old boy presenting presentation, and feet, whilst investigation including histopathological examination of specimen from skin
Childhood cutaneous with post-burn like treatment and biopsy of one scar led to a diagnosis of cutaneous PAN. The child was treated with:
polyarteritis nodosa: An cutaneous scars over back outcomes.  oral prednisolone (prolonged treatment).
unusual presentation. of thighs and buttocks after At 6 months follow-up digital resorption and ulceration appeared halted.
skin culceration.
Vega Gutierrez, Case report. To describe Treatment began with
Rodriguez Prieto & 14-year-old boy diagnosed presentation,  prednisolone (0.5 mg.kg .day ) and prophylactic penicillin.
-1 -1

Garcia Ruiz (2007). with cutaneous PAN treatment and After initial improvement, he continued to have frequent, and sometimes severe, disease flares.
Successful treatment of presenting with a recent flare outcomes.
childhood cutaneous of cutaneous lesions, mild Laboratory investigations revealed elevated ESR and inflammatory cytokines and the treatment
polyarteritis nodosa fever, general malaise and regime changed to:
 intravenous infliximab infusions (5 mg.kg ) at day 0, 15 and 45.
-1
with infliximab. arthralgias.
which resulted in total remission after 20 days. However, 1 month after the last infusion the
patient presented with new flares: this was controlled effectively with
 a single intravenous infliximab infusion (5 mg.kg )
-1

The current treatment, which is well tolerated, is:

 intravenous infliximab infusion (2.5 mg.kg ) every 2 months
-1

27
Ventura,F.; Antunes,H.; Case report. To describe Clinical examination and investigations including histology, immunohistochemical exploration
Brito,C.; Pardal,F.; 11-year-old boy presenting presentation, and radiological evaluation lead to a diagnosis of cutaneous PAN. The patient was treated with
Pereira,T.; Vieira,A.P.after a 3-month history of treatment and  prednisolone (1 mg.kg .day ) which was reduced after 6 weeks and
-1 -1

(2009) Cutaneous extensive livedo reticularis outcomes.

(affecting lower & upper
polyarteritis nodosa in a
extremities and abdomen),
child following hepatitis
B vaccination. asthenia, myalgia and
anorexia: this clinical picture
appeared 1 week after the
third dose of hepatitis B
vaccine injection.
Wahezi, Gomes & Ilowite Case report.
(2010). Cranial nerve 20-month-old girl with
involvement with juvenile PAN presenting with
juvenile polyarteritis cranial nerve III palsy
nodosa: Clinical
manifestations and
treatment.
Wylie, Campbell, Pope, Case report.
Akikusa, Laxer & 15-year-old female
Nicolle (2006). presenting with 2-week
Convergence paralysis history of recurrent
as a manifestation of headaches, episodic
polyarteritis nodosa. vomiting, vertigo and
diplopia. She also had a 6-
week history of episodic
stabbing epigastric pain and
weight loss.
 azathioprine and omeprazole relieved the symptoms, but was not of benefit not much
benefit the cutaneous lesions.
At 2-year follow up the patient was asymptomatic apart from persistent livedo reticular on the
lower extremities whilst laboratory tests were normal. No medication had been taken over the
previous year.
To describe Despite aggressive treatment with immunosuppressant medication for PAN the child developed
presentation, cranial nerve III palsy. Neurological signs and symptoms responded well to:
treatment and  a treatment regime including corticosteroids and cyclophosphamide.
outcomes. However a corticosteroid taper was hindered due to the presence of persistent fevers,
headaches and rash.
Subsequent treatment involved:
 a combination of infliximab and mycophenolate (in addition to corticosteroids)
this was very efficacious and resulted in disease remission and the subsequent withdrawal of
corticosteroid medication.
Full article could not be obtained to clarify some details
To describe Clinical examination and investigation revealed hypertension, bilateral exotropia, neurological
presentation, abnormalities, livedo reticularis on hands and legs, mild elevation of ESR, CRP and platelets,
treatment and and positive antinuclear antibodies. This led to a diagnosis of PAN and a treatment planned
outcomes. initiated including:
 prednisone, aspirin, amlodipine, gabapentin and later azathioprine
At 2-years follow up the patient was in remission, on azathioprine and antihypertensives.

28
SECTION D.2 – PRIMARY RESEARCH: ADULT

Cohort studies
Focused on PAN
Ishiguro, N., & Kawashima, M. (2010). Cutaneous polyarteritis nodosa: A report of 16 cases with
clinical and histopathological analysis and a review of the published work. Journal of
Dermatology, 37(1), 85-93.
Pagnoux, C., Seror, R., Henegar, C., Mahr, A., Cohen, P., Le Guern, V., et al. (2010). Clinical features
and outcomes in 348 patients with polyarteritis nodosa: A systematic retrospective study of
patients diagnosed between 1963 and 2005 and entered into the french vasculitis study group
database. Arthritis and Rheumatism, 62(2), 616-626.

Vasculitides in general
Fain, O., Hamidou, M., Cacoub, P., Godeau, B., Wechsler, B., Paries, J., et al. (2007). Vasculitides
associated with malignancies: Analysis of sixty patients. Arthritis Care and Research, 57(8),
1473-1480.
Haematopoietic stem cell transplantation for vasculitis including behcet's disease and
polychondritis: A retrospective analysis of patients recorded in the European bone marrow
transplantation and European League Against Rheumatism databases and a review of the
literature. Annals of the Rheumatic Diseases, 66(2), 202-207.

Case studies
Cardiac presentation/involvement
Maillard-Lefebvre, H., Launay, D., Mouquet, F., Gaxotte, V., Hachulla, E., De Groote, P., et al.
(2008). Polyarteritis nodosa-related coronary aneurysms. Journal of Rheumatology, 35(5), 933-
934.
Nakamura, Y., Ogino, H., Matsuda, H., Minatoya, K., Sasaki, H., & Kitamura, S. (2008). Multiple and
repetitive anastomotic pseudoaneurysms with polyarteritis nodosa. Annals of Thoracic Surgery,
85(1), 317-319.
Wi, J., Choi, H. H., Lee, C. J., Kim, T., Shin, S., Ko, Y., et al. (2010). Acute myocardial infarction due
to polyarteritis nodosa in a young female patient. Korean Circulation Journal, 40(4), 197-200.
Ziglam, H. M., France, A. J., Evans, A., & Nathwani, D. (2006). Polyarteritis nodosa presenting as a
febrile rash and severe fatal myocarditis. Scottish Medical Journal 51(1), 57

Cutaneous polyarteritis nodosa

Choi, S. W., Lew, S., Cho, S. D., Cha, H. J., Eum, E. A., Jung, H. C., et al. (2006). Cutaneous
polyarteritis nodosa presented with digital gangrene: A case report. Journal of Korean Medical
Science, 21(2), 371-373.
Goolamali, S. I., Gordon, P., Salisbury, J., & Creamer, D. (2009). Subcutaneous calcification
presenting in a patient with mixed connective tissue disease and cutaneous polyarteritis
nodosa. Clinical and Experimental Dermatology, 34(5), e141-e144.
Gupta, S., Duggal, L., & Jain, N. (2006). Cutaneous polyarteritis nodosa - A rare, benign vasculitis.
Journal, Indian Academy of Clinical Medicine, 7(2), 159-160.

29
Kato, T., Fujii, K., Wakabayashi, T., Tanaka, A., & Hidaka, Y. (2006). A case of cutaneous
polyarteritis nodosa manifested by spiking high fever, arthralgia and macular eruption like
adult-onset still's disease. Clinical Rheumatology, 25(3), 419-421.
Kawakami, T., & Soma, Y. (2010a). Therapeutic effect of clopidogrel on cutaneous polyarteritis
nodosa. Archives of Dermatology, 146(1), 100-101.
Kawakami, T., & Soma, Y. (2010b). Use of warfarin therapy at a target international normalized
ratio of 3.0 for cutaneous polyarteritis nodosa. Journal of the American Academy of
Dermatology, 63(4), 602-606.
Komatsuda, A., Kinoshita, K., Togashi, M., Maki, N., Masai, R., Niitsu, H., et al. (2008). Cutaneous
polyarteritis nodosa in a patient with crohn's disease. Modern Rheumatology, 18(6), 639-642.
Lobo, I., Ferreira, M., Silva, E., Alves, R., & Selores, M. (2008). Cutaneous polyarteritis nodosa
treated with intravenous immunoglobulins. Journal of the European Academy of Dermatology
and Venereology, 22(7), 880-882.
Mazokopakis, E. E., Milkas, A. N., Tsartsalis, A. N., Karefilakis, C. M., & Besmertis, L. P. (2009).
Improvement of cutaneous polyarteritis nodosa lesions with hyperbaric oxygen. International
Journal of Dermatology, 48(9), 1023-1025.
Mylona, E., Vadala, C., Papadakos, V., Loverdos, D., Samarkos, M., & Skoutelis, A. (2009).
Cutaneous polyarteritis nodosa in adult onset still's disease. European Journal of Dermatology,
19(6), 621-622.
Rogalski, C. & Sticherling, M. (2007). Panarteritis cutanea benigna - An entity limited to the skin or
cutaneous presentation of a systemic necrotizing vasculitis? Report of seven cases and review
of the literature. International Journal of Dermatology, 46(8), 817-821.
Seung, W. C., Lew, S., Sung, D. C., Hee, J. C., Eum, E., Hyun, C. J., et al. (2006). Cutaneous
polyarteritis nodosa presented with digital gangrene: A case report. Journal of Korean Medical
Science, 21(2), 371-373.
Tehrani, R., Nash-Goelitz, A., Adams, E., Dahiya, M., & Eilers, D. (2007). Minocycline-induced
cutaneous polyarteritis nodosa. Journal of Clinical Rheumatology, 13(3), 146-149.
Tursen, U., Api, H., Kaya, T. I., Cinel, L., & Ikizoglu, G. (2006). Rapid healing of chronic leg ulcers
during perilesional injections of granulocyte-macrophage colony-stimulating factor therapy in a
patient with cutaneous polyarteritis nodosa. Journal of the European Academy of Dermatology
and Venereology, 20(10), 1341-1343.
Ueki, S., Tomimura, S., Mine, Y., Ogawa, F., Sato, S., & Eishi, K. (2008). A case of cutaneous
polyarteritis nodosa accompanied by foot amputation. Nishinihon Journal of Dermatology,
70(1), 19-22.
Zenone, T., Knefati, Y., & Sabatier, J. (2007). Polyarteritis nodosa presenting with jaw claudication
and headache. Joint Bone Spine, 74(3), 301-302.

Gastrointestinal tract presentation/involvement

Cooper, S. C., Olliff, S. P., McCafferty, I., Wigmore, S. J., & Mirza, D. F. (2008). Polyarteritis nodosa,
presenting as life-threatening gastrointestinal hemorrhage in a liver transplant recipient. Liver
Transplantation, 14(2), 151-154.
Maeda, K., Hayashi, Y., Morita, I., Matsuoka, O., Nishiyama, M., Nishimura, H., et al. (2006).
Recurrent Dieulafoy's ulcers in the stomach and colonic perforation caused by polyarteritis
nodosa: Report of a case. Gastrointestinal Endoscopy, 63(2), 349-352.
Mittal, A., Borum, M. L., & Venbrux, A. C. (2006). An unusual case of gastrointestinal symptoms
leading to a diagnosis of polyarteritis nodosa. Practical Gastroenterology, 30(3), 73-74.

30
Siebig, S., Tarne, I. H., Wrede, C. E., Scholmerich, J., Muller-Ladner, U., & Fleck, M. (2007). A case of
recurrent abdominal bleeding due to polyarteritis nodosa despite immunosuppressive therapy.
Scandinavian Journal of Rheumatology, 36(6), 486-488.

Hepatitis B related polyarteritis nodosa

Auguet, T., Barragan, P., Ramirez, R., Quer, J. C., Sirvent, J. J., & Richart, C. (2007). Lamivudine in
the treatment of hepatitis B virus-related polyarteritis nodosa. Journal of Clinical
Rheumatology, 13(5), 298-299.
Ghorbani, G. A., Alishiri, G. H., & Pour, H. K. (2010). High hepatitis B virus load in a patient with
severe polyarthritis nodosa. Hepatitis Monthly, 10(4), 306-309.
Kostina-O'Neil, Y., Jirawuthiworavong, G. V., Podell, D. N., & Lesser, R. L. (2007). Choroidal and
optic nerve infarction in hepatitis C-associated polyarteritis nodosa. Journal of Neuro-
Ophthalmology, 27(3), 184-188.
Lim, M., Kwon, S. R., Lee, S., & Park, W. (2006). Rapid improvement of distal vasculitis in PAN
related to hepatitis B with alprostadil infusion: A case report. Rheumatology International,
26(10), 928-932.
Matsushita, T., Adachi, H., Watanabe, H., Shimoyama, Y., Adachi, T., Sobue, G., et al. (2006).
Classic polyarteritis nodosa presenting rare clinical manifestations in a patient with hemophilia
A. International Journal of Hematology, 83(5), 420-425.
Naniwa, T., Maeda, T., Shimizu, S., & Ito, R. (2010). Hepatitis B virus-related polyarteritis nodosa
presenting with multiple lung nodules and cavitary lesions. Chest, 138(1), 195-197.
Park, S.S., Kim, B.U., Han, H.S., Goo, J.C., Han, J.H., Bae, I.H., et al. (2006). Hemobilia from ruptured
hepatic artery aneurysm in polyarteritis nodosa. Korean Journal of Internal Medicine, 21(1), 79-
82.
Squintani, G., Ferrari, S., Caramaschi, P., Cavallaro, T., Refatti, N., Rizzuto, N., et al. (2009).
Multineuropathy in a patient with HBV infection, polyarteritis nodosa and celiac disease.
Rheumatology International, 29(5), 579-581.
Takeshita, S., Nakamura, H., Kawakami, A., Fukushima, T., Gotoh, T., Ichikawa, T., et al. (2006).
Hepatitis B related polyarteritis nodosa presenting necrotizing vasculitis in the hepatobiliary
system successfully treated with lamivudine, plasmapheresis and glucocorticoid. Internal
Medicine, 45(3), 145-149.

Male reproductive system presentation/involvement

Bush, N. C., Maxwell, K. M., Hamoui, N., & Colegrove, P. (2008). A case of systemic polyarteritis
nodosa with spermatic cord involvement. Nature Clinical Practice Urology, 5(8), 462-466.
Fleischmann, A., & Studer, U. E. (2007). Isolated polyarteritis nodosa of the male reproductive
system associated with a germ cell tumor of the testis: A case report. Cardiovascular Pathology,
16(6), 354-356.
Giannarini, G., Pomara, G., Moro, U., Mogorovich, A., Fabris, F. M., Morelli, G., et al. (2009).
Isolated polyarteritis nodosa of the genitourinary tract presenting with severe erectile
dysfunction: A case report with long-term follow-up. Journal of Sexual Medicine, 6(4), 1189-
1193.
Kolar, P., Schneider, U., Filimonow, S., Burmester, G. R., & Buttgereit, F. (2007). Polyarteritis
nodosa and testicular pain: Ultrasonography reveals vasculitis of the testicular artery.
Rheumatology, 46(8), 1377-1378.
Meeuwissen, J., Maertens, J., Verbeken, E., & Blockmans, D. (2008). Case reports: Testicular pain
as a manifestation of polyarteritis nodosa. Clinical Rheumatology, 27(11), 1463-1466.
31
Pastor-Navarro, H., Broseta-Viana, L., Donate-Moreno, M. J., Pastor-Guzman, J. M., Lorenzo-
Romero, J. G., Segura-Martin, M., et al. (2007). Isolated testicular polyarteritis nodosa. Urology,
70(1), 178.e7-178.e8.
Watanabe, K., Nanki, T., Sugihara, T., & Miyasaka, N. (2008). A case of polyarteritis nodosa with
periurethral aseptic abscesses and testicular lesions. Clinical and Experimental Rheumatology,
26(6), 1113-1115.

Peripheral vascular disease or gangrene presentation/development

Branagan, N. M., Higgins, S. P., Halim, S. A., & Le, T. H. (2009). Systemic polyarteritis nodosa
mimicking pyoderma gangrenosum in a rare association with small lymphocytic
leukaemia/chronic lymphocytic leukaemia. Clinical and Experimental Dermatology, 34(5), e127-
e129.
De Golovine, S., Parikh, S., & Lu, L. (2008). A case of polyarteritis nodosa presenting initially as
peripheral vascular disease. Journal of General Internal Medicine, 23(9), 1528-1531.
Ishikawa, K., Hatano, Y., Otani, Y., Nakata, T., Anan, T., Katagiri, K., et al. (2009). A case of
polyarteritis nodosa with gangrene of the fingers and toes and hypoxemia. Nishinihon Journal
of Dermatology, 71(4), 400-404.
Ninomiya, T., Sugimoto, T., Tanaka, Y., Aoyama, M., Sakaguchi, M., Uzu, T., et al. (2007).
Symmetric peripheral gangrene as an emerging manifestation of polyarteritis nodosa. Journal
of Rheumatology, 34(2), 440-441.

Pulmonary presentation/involvement
Matsuyama, Y., Toyoshima, M., Chida, K., & Suda, T. (2006). A case of recurrent polyarteritis
nodosa associated with pulmonary involvement. Japanese Journal of Chest Diseases, 65(5), 484-
488.
Taj, A., Kanjwal, S., Assaly, R. A., & Hammersley, J. R. (2009). Pulmonary capillaritis in a classical
polyarteritis nodosa. The Internet Journal of Pulmonary Medicine, 11(2)

Renal presentation/involvement
Ahmed, A. K., Mowafi, W., Ellam, T., Khan, A., Angel, C., Wilkie, M., et al. (2008). Acute kidney
injury as a complication of vasculitic polyneuropathy mimicking guillain-barre syndrome with
positive anti-GM1 antibodies. Dialysis and Transplantation, 37(6), 209-211.
El Madhoun, I., Warnock, N. G., Roy, A., & Jones, C. H. (2009). Bilateral renal hemorrhage due to
polyarteritis nodosa wrongly attributed to blunt trauma. Nature Reviews Urology, 6(10), 563-
567.
Huang, M., & Wu, C. (2009). Polyarteritis nodosa and antiphospholipid syndrome causing bilateral
renal infarction. Journal of Rheumatology, 36(1), 197.
Mohammadi, A., Gharaati, M., & Ebadzadeh, M. R. (2006). Spontaneous kidney rupture in a
patient with polyarteritis nodosa. Journal of Research in Medical Sciences, 11(4), 270-272.
Oe, Y., Nakaya, I., Yahata, M., Sakuma, T., & Soma, J. (2010). Classic polyarteritis nodosa
presenting with rapidly progressive renal insufficiency. Clinical Nephrology, 74(4), 315-318.
Soga, Y., Nose, M., Arita, N., Komori, H., Miyazaki, T., Maeda, T., et al. (2009). Aneurysms of the
renal arteries associated with segmental arterial mediolysis in a case of polyarteritis nodosa:
Case report. Pathology International, 59(3), 197-200.

32
Wu, K., & Throssell, D. (2006). A new treatment for polyarteritis nodosa. Nephrology Dialysis
Transplantation, 21(6), 1710-1712.
Yukawa, S., Tahara, K., Yukawa, N., Shoji, A., Tsuji, S., Hayashi, H., et al. (2008). Dramatic
regression of mesenteric abnormalities demonstrated on angiography following prednisolone
and cyclophosphamide combination therapy in a patient with polyarteritis nodosa associated
with sjogren's syndrome. Modern Rheumatology, 18(4), 416-421.

Miscellaneous
Adajar, M. A., Painter, T., Woloson, S., & Memark, V. (2006). Isolated celiac artery aneurysm with
splenic artery stenosis as a rare presentation of polyarteritis nodosum: A case report and
review of the literature. Journal of Vascular Surgery, 44(3), 647-650.
Agoumi, S., Harmouche, H., Tazi, Z. M., Aouni, M., Adnaoui, M., & Maaouni, A. (2007). Periarteritis
nodosa and AL amyloidosis: A case report. Joint Bone Spine, 74(2), 205-206.
Asano, Y., Ihn, H., Maekawa, T., Kadono, T., & Tamaki, K. (2006). High-dose intravenous
immunoglobulin infusion in polyarteritis nodosa. Clinical Rheumatology, 25(3), 396-398.
Balbir-Gurman, A., Nahir, A. M., & Braun-Moscovici, Y. (2007). Intravenous immunoglobulins in
polyarteritis nodosa restricted to the limbs: Case reports and review of the literature. Clinical
and Experimental Rheumatology, 25(1 SUPPL. 44), S28-S30.
Bulbuloglu, E., Kantarceken, B., Yuksel, M., Ciralik, H., Sahinkanat, T., & Kale, I. T. (2006). An
unusual presentation of polyarteritis nodosa: A case report. West Indian Medical Journal, 55(1),
56-59.
Castelino, F. V., Wasfy, J. H., & Collier, D. (2008). A 36-year-old man with paresthesias and a
headache. Arthritis Care and Research, 59(9), 1358-1365.
Chen, H., Yang, C., Hsiao, C., & Chu, C. (2008). Cutaneous polyarteritis nodosa in a patient with
fabry disease. Archives of Dermatology, 144(1), 122-123.
Daikeler, T., Kotter, I., Tyndall, C. B., Apperley, J., Attarbaschi, A., Guardiola, P., et al. (2007).
Das, C. J., & Pangtey, G. S. (2006). Arterial microaneurysms in polyarteritis nodosa. New England
Journal of Medicine, 355(24), 2574.
Emad, Y., Basaffar, S., Ragab, Y., Zeinhom, F., & Gheita, T. (2007). A case of polyarteritis nodosa
complicated by left central retinal artery occlusion, ischemic optic neuropathy, and retinal
vasculitis. Clinical Rheumatology, 26(5), 814-816.
Gait, R. C., Affleck, A. G., Leach, I. H., & Varma, S. (2008). Perinuclear antineutrophilic cytoplasmic
antibody-positive polyarteritis nodosa secondary to minocycline treatment for acne vulgaris.
Journal of the American Academy of Dermatology, 58(5 SUPPL. 1), S123-S124.
Gajera, A., & Kais, S. (2009). HIV polyarteritis nodosa-like vasculitis presenting as chronic
abdominal pain. Clinical Rheumatology, 28(7), 869-872.
Harrold, L. R., & Liu, N. Y. N. (2008). Polyarteritis nodosa presenting as pancytopenia: Case report
and review of the literature. Rheumatology International, 28(10), 1049-1051.
Hayakawa, I., Shirasaki, F., Ikeda, H., Oishi, N., Hasegawa, M., Sato, S., et al. (2006). Reactive
hemophagocytic syndrome in a patient with polyarteritis nodosa associated with epstein-barr
virus reactivation. Rheumatology International, 26(6), 573-576.
Herve, F., Heron, F., Levesque, H., & Marie, I. (2006). Ascites as the first manifestation of
polyarteritis nodosa. Scandinavian Journal of Gastroenterology, 41(4), 493-495.
Hoganson, D. D., Weenig, R. H., & Warrington, K. J. (2008). A 61-year-old man with livedo
reticularis. Arthritis Care and Research, 59(11), 1682-1684.

33
Ikeda, Y., Migita, K., Ito, M., Miyazato, M., Okamoto, K., Eguchi, K., et al. (2006). A case of classical
polyarteritis nodosa complicated by ulcerative colitis. American Journal of the Medical Sciences,
332(3), 137-139.
Kang, M. S., Park, J. H., & Lee, C. W. (2008). A case of overlap between systemic sclerosis and
cutaneous polyarteritis nodosa. Clinical and Experimental Dermatology, 33(6), 781-783.
Katada, Y., Harada, Y., Azuma, N., Matsumoto, K., Terada, H., Kudo, E., et al. (2006). Minocycline-
induced vasculitis fulfilling the criteria of polyarteritis nodosa. Modern Rheumatology, 16(4),
256-259.
Khalil, H. H., Marsden, J., Akbar, N., Gordon, P., Roberts, J., & Schulte, K. (2009). Polyarteritis
nodosa of the breast: Presentation and management. International Journal of Surgery, 7(5),
446-450.
Liao, H., Chien, C., Chen, C., Wang, H., & Huang, D. (2007). Recurrent autoimmune inner ear
disease (AIED) and polyarteritis nodosa in a patient with large cell lung carcinoma. Clinical
Rheumatology, 26(6), 1008-1010.
Miller, S., Miller, E., & Khalidi, N. (2009). Catastrophic antiphospholipid syndrome and polyarteritis
nodosa. Journal of Rheumatology, 36(11), 2619-2621.
Miteva, M., Norgauer, J., & Ziemer, M. (2007). Diplopia and myalgia: Potential heralding symptoms
of polyarteritis nodosa. American Journal of Clinical Dermatology, 8(3), 175-178.
Musuruana, J. L., & Cavallasca, J. A. (2008). Polyarteritis nodosa complicated by antiphospholipid
syndrome. Southern Medical Journal, 101(4), 419-421.
Nakashima, M., Suzuki, K., Okada, M., Takada, K., Kobayashi, H., & Hama, Y. (2007). Successful coil
embolization of a ruptured hepatic aneurysm in a patient with polyarteritis nodosa
accompanied by angioimmunoblastic T cell lymphoma. Clinical Rheumatology, 26(8), 1362-
1364.
Peddi, P., Kalavakunta, J. K., Annakula, M., & Armstrong, J. R. (2010). An unusual complication of
polyarteritis nodosa with massive retroperitoneal hemorrhage: A case report. International
Archives of Medicine, 3(31)
Seja, M., Wacker, F., & Scherubl, H. (2006). Ischemic enteritis caused by hepatitis C virus-
associated polyarteritis nodosa. Clinical Gastroenterology and Hepatology, 4(11), A24.
Shimbo, J., Miwa, A., & Aoki, K. (2006). Cryofibrinogenemia associated with polyarteritis nodosa.
Clinical Rheumatology, 25(4), 562-563.
Stanzani, L., Fusi, L., Gomitoni, A., Roncoroni, M., Villa, P., & Grampa, G. (2008). A case of posterior
reversible encephalopathy during polyarteritis nodosa vasculitis. Neurological Sciences, 29(3),
163-167.
Stromps, J. P., Simunec, D., Kolios, G., Choi, C. Y., & Cedidi, C. C. (2010). A case of fulminant
progressing dermatomyositis panarteritis nodosa (DMPAN). Journal of Plastic, Reconstructive
and Aesthetic Surgery, 63(12), e848-e849.
Sugimoto, T., Kanasaki, K., Koyama, T., Yokomaku, Y., Yasuda, H., Kashiwagi, A., et al. (2007). A
case of myeloperoxidase - antineutrophil cytoplasmic antibody positive-polyarteritis nodosa
complicated by interstitial pneumonia and rapidly progressive renal failure. Clinical
Rheumatology, 26(3), 429-432.
Tanaka, M., Matsuo, K., Nakamura, H., Ishikawa, S., & Matsuyama, K. (2006). Two cases of classical
polyarteritis nodosa associated with MPO-ANCA. Japanese Journal of Nephrology, 48(4), 371-
376.
Taniguchi, Y., Kumon, Y., Hashimoto, K., & Ozaki, S. (2008). Clinical images: Latency of polyarteritis
nodosa until a critical occurrence. Arthritis & Rheumatism, 58(7), 2141.

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SECTION E – OVERVIEWS AND EXPERT OPINIONS

Paediatric polyarteritis nodosa (and vasculitides)

Bilginer, Y., & Ozen, S. (2008). [Polyarteritis nodosa.] In Turkish. Turk Pediatri Arsivi, 43(SUPPL), 17-
20.
Chernick, V. (2006). Pulmonary vasculitides in children. Paediatric Respiratory Reviews, 7(SUPPL.
1), S243-S244.
Dedeoglu, F., & Sundel, R. P. (2007). Vasculitis in children. Rheumatic Disease Clinics of North
America, 33, 555-583.
Dillon, M. J. (2006). Vasculitis treatment - new therapeutic approaches. European Journal of
Pediatrics, 165(6), 351-357.
Dillon, M. J., Eleftheriou, D., & Brogan, P. A. (2010). Medium-size-vessel vasculitis. Pediatric
Nephrology, 25(9), 1641-1652.
Duzova, A., & Bakkaloglu, A. (2008). Central nervous system involvement in pediatric rheumatic
diseases: Current concepts in treatment. Current Pharmaceutical Design, 14(13), 1295-1301.
Eleftheriou, D., & Brogan, P. A. (2009). Vasculitis in children. Best Practice and Research: Clinical
Rheumatology, 23(3), 309-323.
Eleftheriou, D., Dillon, M. J., & Brogan, P. A. (2009). Advances in childhood vasculitis. Current
Opinion in Rheumatology, 21(4), 411-418.
Gilliam, B. E., Reed, M. R., Syed, R. H., & Moore, T. L. (2009). Rheumatic manifestations of epstein-
barr virus in children. Journal of Pediatric Infectious Diseases, 4(4), 321-331.
Gorson, K. C. (2007). Vasculitic neuropathies: An update. Neurologist, 13(1), 12-19.
Herlin, T., & Nielsen, S. (2008). [Primary childhood vasculitis--new classification criteria]. [Primaer
vaskulitis i barnealderen--nye klassifikationskriterier.] Ugeskrift for Laeger, 170(36), 2784-2787.
Kelly, A., & Tizard, E. J. (2010). Vasculitis in children. Paediatrics and Child Health, 20(2), 65-72.
Khubchandani, R. P., & Viswanathan, V. (2010). Pediatric vasculitides: A generalists approach.
Indian Journal of Pediatrics, 77(10), 1165-1171.
Michels, H. (2008). [Azathioprine in paediatric and adolescent rheumatology.] In German. Aktuelle
Rheumatologie, 33(4), 208-210.
Paladini, A., Cappella, M., Mambelli, L., Burnelli, R., & Borgna-Pignatti, C. (2009). [Polyarteritis
nodosa of childhood. A review.] Acta Medica Mediterranea, 25(2), 109-110.
Palit, A., & Inamadar, A. (2009). Childhood cutaneous vasculitis: A comprehensive appraisal. Indian
Journal of Dermatology, 54(2), 110-117.
Saldana, M. D. L. (2009). [Rheumatic diseases in childhood: When should they be suspected? their
initial assessment.] Pediatria Integral, 13(1), 11-19.
Sikorska-Wisniewska, G., Liberek, A., Bako, W., Gora-Gebka, M., Szlagatys-Sidorkiewicz, A.,
Jankowska, A., et al. (2007). [Vasculitis in children]. Medycyna Wieku Rozwojowego, 11(4), 429-
434.
Tullus, K., & Marks, S. D. (2009). Vasculitis in children and adolescents: Clinical presentation,
etiopathogenesis, and treatment. Pediatric Drugs, 11(6), 375-380.

Pharmacological intervention used for polyarteritis nodosa (and vasculitides)

Attar, S. M. (2009). Tetracyclines: What a rheumatologist needs to know? International Journal of
Rheumatic Diseases, 12(2), 84-89.

35
Atzeni, F., Doria, A., Carrabba, M., Turiel, M., & Sarzi-Puttini, P. (2007). Potential target of
infliximab in autoimmune and inflammatory diseases. Autoimmunity Reviews, 6, 529-536.
Atzeni, F., & Sarzi-Puttini, P. (2009). Anti-cytokine antibodies for rheumatic diseases. Current
Opinion in Investigational Drugs, 10(11), 1204-1211.
Braun-Moscovici, Y., Markovits, D., Rozin, A., Toledano, K., Nahir, A.M., & Balbir-Gurman, A.
(2008). Anti-tumor necrosis factor therapy: 6 year experience of a single center in northern
Israel and possible impact of health policy on results. Israel Medical Association Journal, 10(4),
277-281
Chan, A. T., Flossmann, O., Mukhtyar, C., Jayne, D. R. W., & Luqmani, R. A. (2006). The role of
biologic therapies in the management of systemic vasculitis. Autoimmunity Reviews, 5, 273-278.
Eklund, K. K., & Sandler, C. (2007). Antibiotic or anti-inflammatory agent? the double-edged sword
of tetracyclines. Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, 6(4), 253-
263.
Gorson, K. C. (2006). Therapy for vasculitic neuropathies. Current Treatment Options in Neurology,
8(2), 105-117.
Guillevin, L., Pagnoux, C., Guilpain, P., Bienvenu, B., Martinez, V., & Mouthon, L. (2007). Indications
for biotherapy in systemic vasculitides. Clinical Reviews in Allergy and Immunology, 32(1), 85-
95.
Kerns, M. J. J., Graves, J. E., Smith, D. I., & Heffernan, M. P. (2006). Off-label uses of biologic agents
in dermatology: A 2006 update. Seminars in Cutaneous Medicine and Surgery, 25, 226-240.
Mukhtyar, C., Chan, A., & Luqmani, R. (2007). Update on the use of biologics in primary systemic
vasculatides. Expert Review of Clinical Immunology, 3(6), 901-911.
Samuels, J., & Spiera, R. (2006). Newer therapeutic approaches to the vasculitides: Biologic agents.
Rheumatic Disease Clinics of North America, 32, 187-200.

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