A review on the association between inflammatory myopathies and vaccination

Autoimmunity Reviews 13 (2014) 31–39

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Review

A review on the association between inflammatory myopathies and vaccination Joerg-Patrick Stübgen ⁎ Department of Neurology, Weill Cornell Medical College/New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10065-4885, United States

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 1 August 2013 Accepted 16 August 2013 Available online 31 August 2013

Several viruses and vaccines are among the environmental factors implicated as triggers of autoimmune inflammatory myopathies. Case histories report on the onset of dermatomyositis/polymyositis after immunization with various vaccines of patients with probable genetic predisposition. However, retrospective and epidemiological studies failed to ascertain an association between DM/PM and vaccines: no significant increase in the incidence of DM/PM was reported after large vaccination campaigns. The risk for vaccine-induced adverse events may be enhanced by adjuvants. Macrophagic myofasciitis is a novel inflammatory myopathy ascribed to an ongoing local immune reaction to a vaccine adjuvant. Isolated prospective studies showed that the administration of unadjuvanted, non-live vaccine to patients with DM/PM caused no short-term harmful effects to DM/PM immune processes. However, more research is warranted to clarify the incidence of vaccine-preventable infections, harmful effects of vaccination, and the influence of any immunomodulating agents on vaccination efficacy. Vaccination is an important disease prevention tool in modern medicine. This review does not address risk–benefit or cost–benefit analyses, and does not advocate the use of specific vaccines or vaccination programs. Despite a great deal of scientific uncertainty, the concept of a possible causal link between immunization and inflammatory myopathies should not be totally rejected. © 2013 Elsevier B.V. All rights reserved.

Keywords: Inflammatory myopathy Macrophagic myofasciitis Vaccine Immunization Autoimmune

Contents 1. 2.

Introduction . . . . . . . . . Dermatomyositis/polymyositis 2.1. Case reports . . . . . 2.2. Retrospective studies . 2.3. Epidemiological studies 3. Vaccination in DM/PM patients 4. Macrophagic myofasciitis . . . 5. Post-vaccination autoimmunity 6. Conclusion . . . . . . . . . Take-home messages . . . . . . . References . . . . . . . . . . . .

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1. Introduction The idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of immune-mediated, inflammatory muscle diseases. Recognized entities include dermatomyositis (DM), polymyositis (PM),

⁎ Tel.: +1 212 746 2334; fax: +1 212 746 8742. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2013.08.005

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31 32 32 33 34 36 36 37 37 37 37

sporadic inclusion body myositis (sIBM), and necrotizing autoimmune myositis (NAM) [1,2]. The annual incidence of IIM ranges from 2.2 to 7.7 per 1,000,000 people [3]. DM/PM most commonly affects women, and sIBM affects men. Onset of symptoms occurs at any age, but the average age of first manifestations of illness is slightly younger for DM/PM (age 50 years) than for sIBM (age 60 years). The presumed autoimmune pathogenesis of IIM is complicated and incompletely understood, but provides a rationale for offering patients an immunomodulatory and/or immunosuppressive therapy. DM is a

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complement-mediated microangiopathy that results in the destruction of capillaries, hypoperfusion and inflammatory cell stress within the perifascicular regions. In PM and sIBM, cytotoxic CD8-positive T cells clonally expand in situ and invade major histocompatibility-Iexpressing muscle fibers. In sIBM, there are additional degenerative features characterized by vacuolization and an accumulation of stressor and amyloid-related misfolded proteins. Inducible pro-inflammatory molecules (e.g., interleukin 1-β) possibly enhance the accumulation of stressor proteins. NAM is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmunity with macrophages as the final effector cells causing fiber injury. Statininduced necrotizing myositis is increasingly being recognized as a discrete autoimmune entity within the “statin-induced myopathy spectrum” and is associated with the presence of autoantibodies against 3hydroxy-3-methylglutaryl-coenzyme A reductase, and HLA-DRB1*11 [4]. A more complete discussion of disease mechanisms and pathology appears in recent, updated reviews [1,5–9]. There is a combination of genetic and environmental factors that determine susceptibility to IIM [10] e.g., in patients with antisynthetase syndrome variant of IM, the presence of anti-Jo and anti-PL7/PL12 antibodies impacts longterm outcome and prognosis of patients [11]. Several viruses [12] and vaccines [13] are among the environmental factors implicated as triggers for the development of inflammatory myopathies (IM). Evidence from uncontrolled studies suggests that most patients with DM/PM respond to corticosteroid treatment at least to some degree (Class IV evidence) [14,15]. Familiar (azathioprine and/or methotrexate) and less familiar immunosuppressive drugs (cyclosporine, cyclophosphamide, mycophenolate mofetil, or tacrolimus) may offer some empiric/non-evidence-based, “steroid-sparing” effect, but seem to provide little benefit as sole treatment [16]. A controlled study showed that intravenous immunoglobulin (IVIG) is an effective treatment for DM [17], with apparent benefit for patients with PM (Class IV evidence) [18,19]. However, IVIG offers only minimal and transient benefit to a small proportion of patients with sIBM [20,21]. A small (7 patients), pilot study demonstrated the benefit and safety of weekly subcutaneous immunoglobulin in active, refractory IM [22]; controlled studies are needed. Targeted immunotherapy offers a complementary or alternative management approach to immune-mediated illnesses when conventional compounds have reached their limits [23]. Based on the results of a recently published, controlled study with the B celldepleting agent, rituximab, in refractory IM (patients did not reach primary and secondary study end points) [24], further studies are warranted with consideration for a different trial design [25]. Any role for TNF-α antagonists in the therapeutic armamentarium against IM has yet to be established because: (a) results of open-label and placebocontrolled [26] trials varied; (b) these biologicals may exacerbate interstitial lung disease and myositis, and (c) these agents may increase the risk of severe pyogenic and opportunistic infections [15]. The development of vaccines was a major contribution to public health in the modern era [27]. Vaccination is a powerful immune system stimulus that has the theoretical potential to induce or exacerbate immune disturbances that manifest as serological indices of immune system dysregulation or as clinically manifest autoimmune disease [28,29]. There exist several reports in the literature of adverse autoimmune reactions to various vaccines. Mostly, any connection between immunization and autoimmune reaction was temporal, and not causal. Epidemiological studies and controlled studies to evaluate the possible role of vaccines in a variety of autoimmune diseases obtained negative results [30,31]. However, these types of studies lacked the statistical power to rule out an “extremely rare” causal relationship [30,32] as suggested also by published case reports. It seems not unreasonable to propose that vaccines rarely induce autoimmune reactions in presumed genetically or immunologically predisposed individuals [33], but there exists no “unequivocal and irrevocable” evidence of a causative link between vaccination and autoimmunity [34].

The aim of this article is to present in a single text a literature review on a possible relationship between inflammatory myopathies and vaccines. A systematic search was conducted of relevant publications using data bases MEDLINE [PubMed], EMBASE and DynaMed (through July 2013) that included case reports and series, case-control studies, post-marketing surveillance programs, and published analyses of Vaccine Adverse Event Reporting System [VAERS]. Search terms included “inflammatory myopathy”, “myositis”, “vaccine”, “vaccine-associated”, “post-vaccination”, and “autoimmunity”. Article bibliographies were checked to ensure all studies and reports were included. Publications were retrieved, cross-referenced, and analyzed. 2. Dermatomyositis/polymyositis 2.1. Case reports Case histories report on a temporal association between the onset of DM/PM and single or combination vaccination against viruses (hepatitis B [HBV], influenza, smallpox, mumps, rubella, and poliomyelitis) or bacteria (Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheria and Bordetella pertussis) [13] (Table 1). Patient age ranged from 4 to 68 years; the lack of any recognizable age distribution pattern militated against the occurrence of IM as a result of vaccination campaigns directed at specific population age groups. Any risk for vaccine-related IM seemed unrelated to gender (13 male; 11 female). Some patients developed IM after vaccine re-exposure or series, and hinted at a susceptibility to IM due to a “primed”, vigorous immune response. The latency between vaccination and the development of either constitutional symptoms and/or IM varied from 24 h to 2 months; admittedly longer intervals cast some doubt on any temporal association of events, and thus a more tenuous correlation. In 2 patients, PM was associated with interstitial lung disease. Skin and/or muscle biopsy confirmed the inflammatory nature of muscle disease in 12 patients. In 1 patient, biopsy showed severe acute inflammatory exudate within muscle fibers, and also around blood vessels suspicious for a vasculitis component to illness [38]. In a patient with recurrent focal myositis (FM), biopsy showed inflammatory lesions with necrotic fibers undergoing phagocytosis, scattered inflammatory cells, variation in muscle fiber size, and slight perivascular infiltration [49]. Muscle biopsy of a patient with rhabdomyolysis showed no significant inflammatory infiltrate presumably because this post-renal transplant patient was under treatment with maintenance dose prednisolone, cyclosporine A and azathioprine [51]. A hypothesis of an immune-mediated myositis was supported by gradual clinical and laboratory improvement on higher dose prednisolone. Patient treatment varied and included oral steroid treatment with/without oral immunosuppressant and/or tuberculostatic drugs, or was not reported. Patient outcome varied, and in reported cases was mostly favorable. A patient died due to Epstein–Barr-related acute pneumonia [53]. A patient with DM responded rapidly to oral steroid treatment, but over years developed chronic DM (Brunsting type) with multiple calcific plaques of shoulder and pelvic girdles [44]. The patient with FM developed myopathy limited to gastrocnemius muscles 3 weeks after BCG vaccination, followed by recurrences 1 year and 5 years later, respectively; each recurrence responded well to methylprednisolone with/without methotrexate [49]. In 2 patients, rhabdomyolysis with acute, transient renal dysfunction occurred after influenza vaccine administration to patients concurrently treated with HMGCoA reductase inhibitors (statins) with/without a fibrate. Speculatively, the concomitant use of myotoxic drugs increased the risk for muscle breakdown in these patients. However, a prospective, pilot study of 98 patients (52 on statin treatment; 46 untreated) failed to show that influenza vaccination caused clinical or laboratory evidence of myopathy/myositis in patients taking statins [54]. Clues to a possible mechanism of HEP vaccine-associated myositis came from the only detailed study (using indirect immunofluorescence and immunoelectronmicroscopy) on HBV-related PM [55]. HBV antigens

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Table 1 Case reports (chronological order) of (juvenile) DM/PM following vaccination. Reference

Age/Sex

Vaccine

Disease

Latency

Treatment

Outcome

Bitnum [35] Thieffry [36] Machtey [37] Hanissian [38] Cotterill [39] Ehrengut [40]

5.7/M 4/F 13/M 6/M 11/F 6/F 10/M 13/M 11/NR 15/M 12/M 47/F 59/F 68/F 29/F 13/M 68/M 22/M 17/M 57/M 6/F 59/F 60/M 71/F 39/F

SMALL DTAPIPV BCG RUB Multiple DTOX DTOX/SF DTP IP #2 BCG #2 BCG OCV TTOX #2 FLU MU HEP FLU BCG HEP #1/2 FLU HEP H1N1/FLU H1N1/FLU H1N1/FLU H1N1

DM DM DMb PMb DM DM DM DM DM DMb DMb DM DMb DMb PMb DM Rhabdo FMb PMb Rhabdob DMb PM/ILD PM/ILD DM DMb

2 weeks 14 days 2 months 2 days 2 weeks 5 days 5h 10 days 26 days 5–6 weeks 2–3 weeks b1 year 3 weeks 2 weeks 10 days 3 weeks 24 h 3 weeks 21/17 days 1 week 1 week 5 days 1 month 7 days 1 week

NR Steroids Steroid/PAS/INH Prednisone None NR NR NR NK Prednisone/MTX Prednisone/MTX NR Prednisone Prednisolone/AZA None Prednisone None Prednisolone/MTX None Prednisolone NR Steroid/MMF Steroid/MTX/CSP Steroid/IVIG Prednisone

Crippled Improved Recovered Improved Recovered NR NR NR NK Debilitated Deteriorated NR Rapid improvement Responded Recovered Improved NR Recurrent/Remission Transient Improved NR Remission Improved Died Recovered

Pichlera Kåss [41,42] Winkelmann [43] Albert [44] Jani [45] Rose [46] Fernandez-Funez [47] Plotkin [48] Manganelli [49] Ramirez-Rivera [50] Raman [51] Altman [52] Ferri [53]

Stubgena

AZA = azathioprine; CSP = cyclosporine; FM = focal myositis; ILD = interstitial lung disease; INH = isoniazid; MMP = mycophenolate mofetil; MTX = methotrexate; NMK = not known; NR = not reported; PAS = para-aminosalicylic acid; Rhabdo = rhabdomyolysis. BCG = Bacillus Calmette-Guerin; DTP = diphtheria/tetanus toxoids + pertussis; DTAPIPV = diphtheria + tetanus toxoids/acellular pertussis/inactivated polio; DTOX = diphtheria toxoid; FLU = seasonal trivalent influenza; HEP = hepatitis B virus; IP = inactivated polio; MU = mumps; multiple = DT booster, TAB/cholera, polio booster; OCV = oral cold vaccine (mixture of various killed bacteria); RUB = rubella; SF = scarlet fever; SMALL = smallpox; TTOX = tetanus toxoid. a Not published. b Skin/muscle biopsy-confirmed.

(HBsAg and HBcAg) were detected within intact muscle fibers. Major histocompatibility complex (MHC) Class I antigens were co-expressed with viral antigens. An in situ PCR study revealed positive signals within muscle fibers. No viral particles were found so that the infection appeared non-replicative. It seemed likely that HBV infection induced MHC-1 expression, so that viral antigens co-expressed with MHC-1 made infected fibers the target of an immune mediated response. Lastly, genetic susceptibility (e.g., HLA-DR3) possibly predisposed 1 patient to develop DM after HEP vaccination [47]. The importance of any case reports lies in the potential to provide the “first line” of evidence to generate a disease hypothesis [56,57]. Such reports offer fast and inexpensive study, and are frequently the first form of publication. However, the anecdotal nature of reports creates a potential for selection bias, and provides only limited potential to establish causal effects. Therefore, these case reports of IM following administration of vaccines should not be interpreted as proof of cause i.e., association does not equate causation. 2.2. Retrospective studies Retrospective studies showed that recent immunizations were not an important trigger for DM/PM. A single institution, retrospective study reviewed in detail the data of 289 patients with DM/PM diagnosed before 1959 [58]. On re-review of data, only 1 patient had received in the year before onset of DM “cold vaccine” tablets (mixture of killed bacteria) used as prophylaxis against secondary bacterial infection after influenza [43]. These ineffective mixtures are no longer in use, and are unrelated to any in-usage vaccines. In a case-control epidemiologic study (major medical centers and MDA Clinics of northeastern USA) to ascertain prior events, parents were interviewed of 42 cases childhood-onset PM and of age and sex-matched controls [59]. Acute PM was documented in 2 patients

1 month after DPT booster and DPT/IPV/RUB combination, respectively. Extensive review of past medical history, animal exposure history, residential and family history, and immunization revealed no significant differences between the two groups. The only suggestive difference was an increased exposure to bacteriologically confirmed streptococcal diseases in childhood PM compared to controls (p b 0.05). In a retrospective case-control study, an attempt was made to generate new disease hypotheses including any antecedent risk associations for DM/PM with a nationwide survey of 322 cases with onset of disease during the 1985/6 calendar years [60]. Data obtained by recall of events during the 12 months before disease onset in DM/PM cases and in sex-matched sibling controls suggested that antecedent heavy muscular exertion and emotional stress were possible risk factors for DM/ PM. It appeared that vaccinations (as well as toxic exposures, symptoms of allergic phenomena, throat infection, upper respiratory infection, and malignancy) were either neutral or negatively associated with risk for DMPM. These findings raised potentially interesting etiologic questions, but did not fully allay existing doubts. In a retrospective study, questionnaires were sent to rheumatology departments of 9 French hospitals in order to ascertain the occurrence of autoimmune inflammatory systemic diseases (lasting longer than 1 week) within 2 months after immunization with HEP [61]. The study included 22 patients, but none with DM/PM. Nevertheless, it was concluded that a causal relationship between HEP and any observed rheumatic manifestations could not be established with any certainty. In a retrospective, national study, physicians were asked to complete questionnaires regarding preceding infections, medications, immunizations, and any other exposure within 6 months of onset of illness for 285 patients with probable/definite juvenile IM [62]. Recorded exposure was ascertained in 60% of patients. Of the total, recorded exposures included: (a) immunizations 11%; (b) infections 44%; (c) medications 18%; (d) stressful life events 11%, and (e) sun

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exposure 7%. A higher frequency of documented exposure (odds ratio 95%; confidence interval 3.4) was determined for patients with an older median age at diagnosis, with longer delay to diagnosis, or with serum anti-SRP autoantibodies. While certain environmental factors were temporally associated with the onset of juvenile IM; causality was not established. This author reviewed multiple, large patient-number retrospective studies from various countries specifically to ascertain any other reports of a temporal relationship between onset/diagnosis of DM/PM and presumed precipitating events, including immunization. Studies included: (a) 40 DM and 35 PM adult patients from multiple centers in Singapore [63]; (b) 30 DM and 17 PM adult patients from a single institution in Poland [64]; (c) 11 DM and 31 PM adult patients from a single institution in France [65]; (d) 23 JDM/DM and 8 PM patients from a single institution in Puerto Rico [66]; (e) 50 DM and 20 PM adult patients from multiple centers in Tunisia [67]; (f) 57 JDM identified from the National Patient Register in Denmark [68], and (g) 19 DM and 11 PM adult patients from a single institution in Jordan [69]. Some studies reported on malignancy as a potential trigger for DM/PM, but no study reported specifically on vaccination anamnesis. Therefore, it is not known whether any association was not addressed or not determined. 2.3. Epidemiological studies The Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) established the VAERS program (in 1990) in response to the National Childhood Vaccine Injury Act [NCVIA] (of 1986). VAERS is a post-marketing, national vaccine safety surveillance program that collects information about adverse events after

administration of licensed vaccines in the US, and is meant to serve as an “early warning system” [www.vaers.hhs.gov]. The inclusion of any reported adverse event in VAERS data does not imply causality [70]. It is impossible to reliably estimate the incidence of vaccinerelated adverse events because the data reported to VAERS consist of a series of single case reports, without a case cohort control group from an uncertain population sample size. VAERS is subject to the limitations of any voluntary, passive surveillance system such as: (a) underestimation (under- or non-reporting); (b) differential reporting (reporting increases in the initial few years after vaccine licensure); (c) stimulated reporting (reporting increases after an alleged similar adverse events become known); (d) reporting of coincidental events (unknown type or duration of concomitant medical condition); (e) dubious data quality and completeness (varies between physicians or institutions), and (f) unknown differences between the post-marketing surveillance groups and the clinical trial-selected populations. There exist no reports in the literature of a significant increase in the incidence of DM/PM after any large vaccination campaigns. On an analysis of available data (from a passive reporting system centrally coordinated by the CDC Surveillance and Assessment Center before establishment of VAERS) there was no evidence of an increase in the number of DM/PM cases observed and reported among the 43.3 million civilians immunized with the A/NJ/76 (swine flu) vaccine from October 1 to December 16, 1976, in the United States [71]. Among nearly 1 million vaccinated Army and Navy personnel, there was likewise no increase in the incidence rate of DM/PM. Furthermore, there was no indication of an increase in the number of DM/PM cases diagnosed at major medical institutions (the Mayo and Cleveland clinics; the Cleveland Metropolitan and the Massachusetts General hospitals) during or

Table 2 Age group

Nr/Sex

Vaccine

Interval

Recovery

Nr/Sex

Vaccine

Interval

Recovery

1/F

FLU

31–60 days

No

1/F 1/F

HPV4 HPV4

7 days 211–240 days

No NK

1/F I/F

HPV4 MNQ

15–30 days 211–240 days

NK NK

1/F 1/M 1/F 1/F 1/F 1/M

FLU FLU HEP HPV4 MNQ TD

0 day NK NK 15–30 days 15–30 days 2–3 years

Yes NK No No No NK

1/M 2/M 1/F 1/M 1/M 1/F

FLU HEP HAV LYME TD TDAP

121–150 days NK 15–30 days 0 day 15–30 days 15–30 days

Yes Yes No No No No

1/M 1/M 1/F 1/F 1/F 1/M 1/F 1/F 1/M 1/F

ANTH FLU FLU FLU FLU HEP HAV MEN TTOX YF

3–4 years 1 day 0 day 10–14 days 271–300 days 1–2 years NK NK NK NK

No Yes No No No NK NK NK NK NK

1/M 1/F 1/F,1/M 1/F 2/M 1/F 1/F,1/M 1/F 1/F

DTAPIPV FLU FLU FLU HEP HEP IPV TD TYP

10–14 15–30 1 day 31–60 10–14 NK NK NK NK

No Yes No No No NK NK NK NK

1/M 1/M

FLU PPV

1 day 31–60 days

Yes No

1/M

FLU

31–60 days

1/M

FLU

3 days

No

1/F

FLU

0 day

NK

3–6 years 12–17 years

17–44 years

44–65 years days days days days

65–75 years No

N75 years Unknown P.S. Because some events had multiple vaccinations and symptoms, a single event may have counted for multiple entries in this table, hence total count is greater than 33 (the number of events found). ANTH = anthrax; DTAPIPV = diphtheria/tetanus toxoids/acellular pertussis/inactivated polio; HAV = hepatis A virus; HEP = hepatitis B virus; HPV4 = human papilloma virus quadrivalent; IPV = inactivated polio vaccine; MEN = meningococcal polysaccharide; MNQ = meningococcal conjugate; PPV = pneumococcal polyvalent; TD- tetanus + diphtheria toxoids; TDAP = tetanus + reduced diphtheria toxoids/acellular pertussis; TTOX = tetanus toxoids; TYP = typhoid VI polysaccharide; YF = yellow fever.

J.-P. Stübgen / Autoimmunity Reviews 13 (2014) 31–39

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Table 3 Age group

Nr/Sex

Vaccine

Interval

Recovery

Nr/Sex

Vaccine

Interval

Recovery

1/M 1/F 1/M 1/M 1/F 1/M 1/F 1/M

DTAP DTAP HEP HEP HIBV IPV MMR PNC

0 day 10–14 days 3 days 2–3 years 10–14 days 3 days 10–14 days 0 days

Yes No NK No No Yes No Yes

1/M 1/M 2/F 1/M 1/M 1/M 1/F 1/M

DTAP DTP HEP HIBV HIBV IPV MMR PNC

3 day 2–3 years 91–120 days 3 days 2–3 years 2–3 years NK 3 days

Yes No No Yes No No No Yes

1/M 1/M 1/F 1/F 1/F 1/F 1/F

DTAP FLU FLUN HEP HAV MMR VARCEL

1 day NK 8 days 151–180 days 0 day 0 day 0 day

No No No Yes NK NK NK

1/F 1/F 1/F 1/F 1/M 1/M 1/M

DTAPIPV H1N1 HEP HEP IPV MMR VARCEL

0 days 15–30 days 10–14 days NK 1 day 1 day 1 day

NK NK No NK No No No

1/F 1/F 1/F 1/M

HEP HEP HIBV TD

31–60 days 151–180 days 5–6 years 0 day

No No Yes No

1/M,2/F 2/F 1/F 1/F

HEP HEP MMR VARCEL

91–120 days NK 5–6 years 5–6 years

No, No, NK NK Yes Yes

1/F

HEP

10–14 days

No

2/F

HEP

31–60 days

NK

1/F 1/F 1/M,1/F 1/F 1/F 1/F 1/F,1/M

DTAP HEP HEP HAV HPV4 MMR TD

2 days 15–30 days NK NK 10–14 days NK NK

NK Yes No No No No No,NK

1/F 1/M,1/F 1/F 2/F 1/F 1/F 1/F

FLU HEP HAV HPV4 HPV4 MNQ VARCEL

10–14 days NK 2 days 2 days 121–150 days 2 days 2 days

No Yes NK NK No NK NK

1/M 1/F 1/F,1/M 1/F 1/F 1/F 2/F 1/F 2/F 1/F

FLU FLU FLU HEP HEP HAV HPV4 MNQ TD TYP

0 day 7 days NK 15–30 days 6–7 years 15–30 days 15–30 days 15–30 days NK NK

Yes NK No,NK No NK No No,NK No No No

1/F 1/M 1/F 1/F 2/F,2/M 1/F 1/F 1/F 1/F 1/F

FLU FLU HEP HEP HEP HPV4 HPV4 MNQ TDAP YF

1 days 121–150 days 10–14 days 151–180 days NK 0 day NK NK 15–30 days NK

No NK No NK NK No NK No No No

1/M 1/F 1/F 1/F 1/M 1/F 1/F 1/M 1/M

ANTH FLU FLU FLU HEP HEP HEP PPV VARZOS

1 day 1 day 5 days 271–300 days 1 day 31–60 days NK 10–14 days 91–120 days

No No No No No No NK No NK

1/F 1/F 1/F 2/F 1/M 1/F 1/F 1/F

DTP FLU FLU FLU HEP HEP HAV TD

1–2 years 4 day 8 day NK 15–30 days 1–2 years 1–2 years 0 day

No No No NK NK No No No

1/M 2/F

FLU TTOX

NK NK

Yes NK

2/F

HEP

NK

NK

1/F 1/M,3/F 1/F 1/F

HEP HEP HPV4 TBE

15–30 days NK NK NK

No NK NK No

1/F 1/F 1/NK 1/F

HEP HPV4 MMR TDAP

NK 0 day NK NK

No No NK No

b3 years

3–6 years

6–9 years

9–12 years 12–17 years

17–44 years

44–65 years

66–75 years

Unknown

P.S. Because some events had multiple vaccinations and symptoms, a single event may have counted for multiple entries in this table, hence total count is greater than 33 (the number of events found). ANTH = anthrax; DTAPIPV = diphtheria/tetanus toxoids/acellular pertussis/inactivated polio; HAV = hepatitis A virus; HEP = hepatitis B virus; HPV4 = human papilloma virus quadrivalent; IPV = inactivated polio vaccine; MEN = meningococcal polysacchride; MNQ = meningococcal conjulate; PPV = pneumococcal polyvalent; TD = tetanus + diphtheria toxoids; TDAP = tetanus + reduced diphtheria toxoids/acellular pertussis; TTOX = tetanus toxoids; TYP = typhoid VI polysaccharide; YF = yellow fever.

following the 1976 national immunization program. The reviewers concluded that their review of the literature and analysis of data failed to ascertain that this vaccine (or any prior influenza vaccination program) represented an additional risk factor for DM/PM.

A prospective, case-control epidemiological study compared serious autoimmune adverse events (reported to VAERS) following administration of HEP vaccine to an unexposed tetanus-containing vaccine group [72]. Groups were matched for age, sex, and year of vaccination.

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Autoimmune conditions were analyzed that had previously been identified from case reports. HEP vaccination of adults was associated with an increased odds risk to develop a variety of serious autoimmune adverse events. However, the risk for IM was not analyzed, because myositis had not previously been identified as a HEP vaccineassociated at-risk disease based a priori from case reports to VAERS. A search of the VAERS database (current up to 12 June 2013) conveniently through website www.medalerts.org/vaersdb/findfiled.php revealed 33 events classified as PM (Table 2), 85 events as DM (Table 3); the single reported case of sIBM occurred in a man (age category 44– 65 years) who developed myositis at an interval of 151–180 days after HEP vaccination. It is worth re-emphasizing that these unverified reports do not establish or imply that myositis was caused by vaccination. A look at raw data showed that no age group was spared and that no age group was particularly susceptible to myositis following vaccination. Post-vaccination myositis did not occur disproportionately in patient age groups that partake in national vaccination schedules/programs. No noticeable gender skewing was noted, except for vaccine programs specifically aimed at females e.g., HPV4. No single vaccine or vaccine preparation stood out as a particular culprit. The latency between immunization and onset of myositis varied considerably. Long intervals between events cast doubt on the criterion of a temporal association. However, for the purpose of reporting VAERS specifies no time limit for the interval between vaccination and onset of illness so that events that occur long after vaccination are not be missed. The database outcome parameter option available was “yes” or “no” for recovery, so that the spectrum of patient outcome could not be fully assessed. As with any passive voluntary reporting system, full set of chosen data was often missing. Details of individual patient reports are available if VAERS identification numbers are known, but were not pursued for the purposes of this review. The limitations of VAERS data do not establish epidemiological support for postvaccination DM/PM, yet the concept of post-vaccination DM/PM should not be categorically rejected.

that determines seroconversion/-protection rates and/or the risk for generating autoantibodies and/or autoimmune disease relapses; the influence of concomitant immunotherapy on post-vaccination autoimmune ‘flare-up’ has not been systematically studied. However, several studies show no significant or consistent increase in the risk of post-vaccination disease exacerbation and/or autoantibody production in patients under treatment for various autoimmune conditions [77–82]. Only limited data exist on the safety and efficacy of vaccines in patients with JDM. A single institution, prospective, controlled study showed that vaccination with non-adjuvanted, non-live H1N1/2009 vaccine caused no short-term (21 days) harmful effects to JDM (30 patients with mean age 15.5 years) disease course; however, seroconversion rate was hampered particularly by chronic disease and concomitant immunosuppressive therapy [83]. Clinical (JDM scores) and laboratory (serum enzyme levels) parameters remained stable during study period. A lower rate on seroconversion as recorded in treated JDM patients compared to controls (p = 0.039). However, seroprotection was similar in both groups. Vaccine-related adverse events were mild and similar in JDM patients and controls. Thus, non-adjuvanted influenza vaccination seemed safe, but effective vaccination may require a different protocol for chronic JDM under immunosuppression. A second study included 6 patients with JDM immunized with a non-live vaccine against seasonal influenza, and also reported no vaccine-related serious adverse events or disease flares [84]. A third study reported no vaccine-related adverse events in 4 patients with JDM (on prednisone and MTX) immunized with live attenuated vaccine against Varicella zoster; 2 patients responded with protective serum antibody levels [85]. Adequately powered studies of live and non-live vaccination in patients with pediatric rheumatic disease are needed to clarify any safety and efficacy concerns [86].

3. Vaccination in DM/PM patients

There is growing appreciation of an “autoimmune-like clinical syndrome induced by adjuvants” (ASIA or Shoenfeld's syndrome) comprised of four medical conditions (the macrophagic myofasciitis syndrome, siliconosis, Gulf war syndrome, and post-vaccination phenomena) all of which are characterized by an hyperactive immune response (in reaction to a common pathogenic denominator) accompanied by a similar complex of symptoms and signs [87–90]. Macrophagic myofasciitis (MMF) has been reported following vaccination, and is attributed to the aluminium hydroxide (a nanocrystalline compound forming aggregates) used as an immunological adjuvant in some vaccines since 1927 [91–94]. Although generally well tolerated, aluminium hydroxide (alum) occasionally causes disabling health problems in presumably genetically susceptible individuals e.g., subjects carrying the HLA-DRB1*01 [93,94]. A small proportion of vaccine recipients present with delayed-onset, diffuse, steroidresponsive arthromyalgia, chronic fatigue [95,96] and rare central nervous system demyelinating lesions [97] that were difficult to reconcile with the long-term persistence of an inoculation site intramuscular localized immune reaction [98]. MMF has been reported mainly in adults [13], but also in children [96,99,100]. In a series of 50 patients with MMF, 86%, 58% and 19% had received HEP, TTOX and HAV vaccines, respectively, at a median of 36 months before the biopsy [92]. Deltoid muscle injection site histology shows granular periodic acid-Schiff reagent positive macrophage infiltration intermingled with lymphocytes; macrophages may show intracytoplasmic inclusions containing alum crystals [92]. The WHO Vaccine Advisory Committee proposed as a working hypothesis that MMF can occur in “a predisposed subset of individuals with an impaired ability to clear aluminium from the deltoid muscle” after vaccination [101]; changes in vaccination practices (e.g., novel and alternative vaccine adjuvants) were deemed unwarranted.

The effects of vaccination on established DM/PM disease course was studied. A single-institution, controlled, prospective study showed that vaccination with non-adjuvanted, non-live H1N1/2009 vaccine caused no short-term (21 days) harmful effects to adult (mean age 43.1 years) IM (37 DM and 21 PM) disease course, and showed adequate immunogenicity in IM patients concurrently treated with various maintenance immunoregulatory drugs [73]. Clinical (patient's and physician's analog scale, and manual muscle test) and laboratory (serum levels of creatine kinase and aldolase) parameters remained stable throughout the study. Seroconversion rates were comparable in the IM and control groups. Vaccine-related adverse effects were mild and similar in the DM/PM and control groups. Long-term adverse effects were not studied. Thus, non-adjuvanted, non-live influenza vaccination seemed safe and effective in adult patients with DM/PM. The European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) were recently published [74]. Patients with AIIRD were deemed at increased risk to develop (complicated) infectious diseases; while vaccinations seemed to reduce this risk, questions and controversies remain regarding the risk-benefit for the individual patient [75]. An expert panel concluded that more research was necessary to clarify the incidence of vaccine-preventable infections, harmful effects of vaccination, and the influence of any immunomodulating agents on vaccination efficacy [76]; recommendations were offered in attempts to also limit the potential risk of clinical and/or serological exacerbation of the underlying AIIRD after vaccination. In the complicated setting of vaccinating patients with more-or-less active autoimmune disease, treatment with any of a variety of immunomodulating/-suppressive drugs/agents is but one variable in a complicated immune response

4. Macrophagic myofasciitis

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Epidemiological data do not exist on the incidence of MMF in the population that received alum-containing vaccines. Despite public concerns over the safety of alum, it is unlikely that this adjuvant will be removed from vaccines because replacement with another booster would be costly and time consuming [102].

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inoculation site inflammatory myopathy ascribed to an ongoing local immune reaction to aluminium hydroxide used as an immune adjuvant in some vaccines; changes in vaccination practices seem unwarranted because these vaccines provide enormous benefit for public health worldwide.

5. Post-vaccination autoimmunity Take-home messages The mechanisms of autoimmune phenomena after vaccination may be analogous to those following natural infections, so that biological plausibility may be based on [32,103–106]: (a) molecular mimicry (due to structural homology between an infectious and host antigenic components) [107]; (b) epitope spreading (appearance of a new antibody or T cell response to different epitopes on the same or different antigen) [108]; (c) bystander activation (priming of microbial antigenspecific T cell in a conducive immune environment) [109]; (d) release of cryptic epitopes [110]; (e) reactivation of memory T cells [111]; (f) activation of superantigens (infectious particles may cross-link the T cell receptor and MHC molecule independent of specific antigen recognition) [112], or (g) direct inflammatory damage (infectious agents may cause tissue injury, releasing autoantigens; these are processed and presented by antigen-presenting cells, thereby priming autoreactive T cells) [113]; (h) formation of immune complexes [114]; (i) expression of MHC antigens on non-immune cells (virus infection results in expression of HLA Class I on non-immune cells which may lead to presentation of autoantigens and recognition by autoreactive T cells) [115], and (j) patient genetic predisposition to autoimmunity [116,117]. These pathogenic mechanisms are not mutually exclusive, and any may be relevant depending on the stage of disease evolution [113]. Any invoked mechanism likely also depends on the presumed pathogenesis of any particular immune disorder. The association between a single autoimmune phenomenon (i.e., IM) and different vaccine types hints at the possibility that a common denominator (e.g., an adjuvant) triggers the syndrome [118]. Adjuvants are administered simultaneously with vaccines to induce a more vigorous immune response to the vaccinated antigens. It appears that adjuvants mimic specific sets of conserved molecules such as bacterial polysaccharides, endocytosed nucleic acids and unmethylated CpG-DNA that activate the innate immune response [118,119]. Adjuvants may exert immune-enhancing effects by: (a) translocation of antigens to lymph nodes thereby enhancing antigen recognition by, and stimulation of, T cells; (b) antigen protection so that extended delivery and exposure to the immune system enhances B and T cell production; (c) increase of local injection site reaction that facilitates release of stimulatory chemokines by T cells and mast cells; (d) promoting release of inflammatory cytokines thereby recruiting B and T cells to infection sites and increasing translational events, or (e) interaction with pattern recognition receptors on leukocyte (accessory cell) membranes [28,29,118,120,121]. 6. Conclusion The low incidence of DM/PM makes for difficult study. Based on the temporal relationship between the onset of DM/PM and administration of various vaccines, and some evidence from biological plausibility studies, the concept of an immune-mediated attack against skeletal muscle after immunization of genetically susceptible individuals probably exists, but is rare. Proof of causality in humans would require large, complicated and expensive epidemiological studies, which limits feasibility, though appropriate animal models of post-vaccination IM could help to determine disease risk and mechanism. In adult patients with AIIRD (including DM/PM), more research is needed to clarify the incidence of vaccine-preventable infections, harmful effects of vaccination, and the influence of any immune modulating agents on vaccination efficacy. MMF is a novel

• The development of vaccines was a major contribution to public health in the modern era. • Immunization programs have had a remarkably good safety record and have greatly reduced the morbidity and mortality from several naturally occurring infectious diseases. • The small risk for any vaccine-induced adverse immune events may be enhanced by adjuvants. • The phenomenon of post-vaccination IM likely exists, but the occurrence is rare. • Post-vaccination IM is presumably an autoimmune phenomenon. • In AIIRD (including DM/PM), more research is needed to clarify the incidence of vaccine-preventable infections, harms of vaccination, and the influence of any immunomodulating agents on vaccination efficacy. • Macrophagic myofasciitis is a novel injection site granulomatous IM ascribed to an ongoing local immune reaction to aluminium hydroxide vaccine adjuvant.

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Fast infusion of rituximab is safe in patients with rheumatic diseases Rituximab (RTX) is effective as a second line therapy for patients affected with Rheumatoid Arthritis (RA) and, although it is used as off-label indication, is reported to be effective also in systemic lupus erythematosus (SLE) and vasculitis. Infusion reactions are reported to occur in 30-35% of cases, especially during the first infusion and, due to this potential risk, slow infusion rate is currently recommended in rheumatology practice. The infusion usually takes an average of 400 minutes which is time and health care resources consuming and discomforting for patients.Can M et al (Clin Rheumatol 2013;32:87-90), following the good experience reported in oncology with fast infusion rate, administered RTX to 68 patients (60 RA, 5 SLE, and 3 vasculitis) in 255 minutes. Infusion reaction were observed in 14,7% of patients. The most frequent symptoms reported were pharyngeal discomfort, dysphagia and vertigo; in all cases reactions were mild.A faster infusion rate seems not to affect the safety of RTX in this cohort of patients with rheumatic disease. This treatment schedule could be time saving for patients and health care personnel and could increase the number of infusions chairs available for patients during daily clinical practice.