Immunization of adolescent girls with the human papillomavirus (HPV) vaccine was initiated to prevent uterine and cervical cancers [1] [2] . In April 2013, two types of vaccines (Gardasil^®-CSL/Merck and Cervarix^®-GSK) were widely introduced for use in Japanese girls aged 13 to 16 years. The adverse events that occur after HPV vaccination commonly include fever, headache, and local pain at the injection site [3] . In addition, a relatively high incidence of chronic limb pain, frequently complicated by violent, tremulous involuntary movements, has been noted in Japanese girls after receiving vaccination.

Our previous report showed that the main disorders observed in these post-vaccination girls consisted of complex regional pain syndrome (CRPS)I, orthostatic hypotension (OH), and postural orthostatic tachycardia syndrome (POTS), all of which were ascribed to peripheral sympathetic nerve dysfunction [4] . Similar data were recently reported from Denmark [5] , and for the pathophysiology of this dysautonomia, small fiber neuropathy is surmised to be an underlying disorder [6] . Migrating joint pains or arthralgias were frequent systemic reactions to HPV vaccination [7] , but usually lacked any inflammatory findings, including elevated serum C-reactive protein (CRP) levels. These joint pains were therefore interpreted as a manifestation of CRPS-I [8] [9] . We here describe two Japanese patients who developed true joint lesions after HPV vaccination.

In Japan, 8.75 million doses of HPV vaccine, predominantly Cervarix^®, have been administered during the past 3 years. Between December 2009 and March 2013, 698 cases were reported to have had serious adverse reactions. Among these reactions, syncope, transient unconsciousness, anaphylactic shock, severe limb pain with paresis, and/or involuntary movement were the most frequent manifestations. Eleven cases with arthritis have been reported, in which all of the patients received Cervarix^® (incidence of arthritis: 0.016%), but the details of these joint lesions were not reported (information from the Ministry of Public Health, Labour and Welfare, Japan; see http://www.mhlw.go.jp/stf/shingi/0000033881.html). Arthritis is known to be a post-vaccination phenomenon [10] . Diphtheria-tetanus-pertussis (DTP) and measles-mumps-rubella (MMR) vaccines are representative causative agents. Aberrant autoimmune responses after vaccination are surmised to be responsible for this form of arthritis [11] . Experimental animals immunized by vaccines were found to produce several different autoantibodies, including lupus-associated ones [12] . Some adjuvants such as aluminium salts may play an important role in the pathogenesis of these immune mediated disorders [13] [14] . Recently, the new term autoimmune (autoinflammatory) syndrome induced by adjuvants (ASIA) has been proposed to cover four similar conditions consisting of silicosis, the Gulf War syndrome, the macrophagic myofasciitis syndrome, and post-vaccination phenomena [10] [15] . In the diagnostic criteria for ASIA, arthralgia and/or arthritis is listed as a typical manifestation [10] . The presence of some HLA types such as HLA-DRB1 or DQB1 seems to be a diagnostic hallmark for ASIA [10] [16] . In addition, in a small number of Japanese girls, the DPB1*05:01 allele was reported to be significantly associated with the post-HPV vaccinated neurological disorder [17] . The epidemiological characteristic of ASIA among the girls who received HPV vaccination was evaluated based on the Vaccine Adverse Reporting System (VAERS). The estimated reporting rate was 3.6 cases per 100,000 doses, and the significant odds ratio of developing SLE, vasculitis, and arthritis were 5.3 (1.5 - 20.5), 4 (1.01 - 16.4), and 2.5 (1.4 - 4.3), respectively [18] .

In our two cases, joint lesions developed soon after HPV vaccination, suggesting that the disorders were causally related to HPV vaccination. Case 1 showed transient mono-arthropathy without any specific treatment, while case 2 followed a pattern of recurrent polyarthritis and finally required immunomodulating therapy. Thus, in the latter case, the clinical picture and treatment response closely resembled those of JIA [19] , although the patient lacked destructive joint lesions or systemic involvement of visceral organs. In the Japanese reports of adverse events after HPV vaccination, the incidence of arthritis was low. Thus, some physicians insist that JIA independently developed in these girls [3] . This possibility cannot be certainly ruled out, as JIA or rheumatoid arthritis is one of the most common forms of autoimmune arthritis, affecting approximately 0.5% - 1.0% of the general population [20] . In contrast, no specific diagnosis for untoward vaccine reactions has been established. The HLA genotype obtained from case 2 seemed not determinative of the final diagnosis. We therefore surmise that a significant number of cases with this disorder were misdiagnosed as having CRPS-I, fibromyalgia, or psychogenic pain [21] . The pathogenic mechanism of the occurrence of serious adverse reactions, including dysautonomia, after HPV vaccination remains unclear [6] . Nevertheless, to respond practically, clinicians should be aware of the possible association between HPV vaccination and the development of arthropathy or arthritis. To our knowledge, this is the first report describing the details of joint lesions that developed after HPV vaccination.

HPV vaccination may occasionally induce true joint lesions.

This work was supported by a Health and Labour Science Research Grant on Intractable Diseases (Pathogenesis and Diagnostic Accuracy of Neuropathic Pain, 23170301 to S.I.) from the Ministry of Public Health, Labour and Welfare, Japan.

None.

RyutaAbe,TomomiKinoshita,AkiyoHineno,Shu-ichiIkeda, (2016) Monoarthropathy or Polyarthritis in Adolescent Japanese Girls Who Received Immunization with the Human Papillomavirus Vaccine. Case Reports in Clinical Medicine,05,109-114. doi: 10.4236/crcm.2016.53020