Adult Subthreshold spectrum correlates to Post-traumatic Disorder spectrum in patients with C. Carmassi1, A. Cordone1, A. Ciapparelli1, C.A. Bertelloni1, F.M. Barberi1, C. Foghi1, V. Pedrinelli1, V. Dell’Oste1, L. Bazzichi2, L. Dell’Osso1

1Psychiatric Clinic, Department of ABSTRACT Moreover, through an examination of Clinical and Experimental Medicine, Objective. Fibromyalgia (FM) is an the correlation between AdAS spec- University of Pisa; increasingly prevalent disorder that trum and TALS-SR scores, significant 2Rheumatology Unit, Department of usually shows a chronic course and a correlations between the total score of Clinical and Experimental Medicine, University of Pisa, Italy. disappointing therapeutic response in the two instruments has emerged. The which psychiatric features seem to play correlation resulted to be particularly Claudia Carmassi, MD, PhD Annalisa Cordone, MD a relevant role. Most recently, the rela- significant between TALS-SR scores Antonio Ciapparelli, MD tionship between FM and Post-traumat- and non-verbal communication do- Carlo Antonio Bertelloni, MD ic Stress Disorder (PTSD) has gained main of the AdAS and between hyper- Filippo Maria Barberi, MD interest since several studies demon- hypo reactivity to sensory input domain Claudia Foghi, MD strated a higher rate of PTSD, both full and several TALS-SR domains. Virginia Pedrinelli, MD blown and partial, and Post-traumatic Conclusion. These results highlight the Valerio Dell’Oste, MD Stress spectrum symptoms. While the clinical relevance of autistic traits in Laura Bazzichi, MD Liliana Dell’Osso, MD relationship between higher burden of FM patients with PTSD. In this regard, autistic symptoms and PTSD is reported we may claim a potential role of abnor- Please address correspondence to: Annalisa Cordone, in literature, the relationship between mal processing of sensory input and Department of Clinical FM and symptoms is deficits in non-verbal communication and Experimental Medicine, still unexplored. In this study we inves- in explaining this association. University of Pisa, tigated both post-traumatic and autistic Via Roma 67, spectrum in a sample of FM patients Introduction 56126 Pisa, Italy. with the aim of exploring the relation- Fibromyalgia (FM) is a widespread E-mail: [email protected] ships between these dimensions. and challenging characterised Received on February 26, 2020; accepted Methods. One hundred and nineteen by multifaceted clinical phenotypes, in in revised form on May 18, 2020. patients with FM, diagnosed according which pain is the defining feature (1- Clin Exp Rheumatol 2021; 39 (Suppl. 130): S20-S26. the American College of Rheumatol- 4). Accordingly, ICD-11 defines FM as ogy 2010 criteria, were consecutively a chronic primary pain syndrome (5), © Copyright Clinical and enrolled at the Unit of Rheumatology, Experimental Rheumatology 2021. and the belonging of this pathology to University of Pisa, Italy. a defined field of specialty is the matter Key words: fibromyalgia, Assessments included: the Trauma And of long-standing debates (6-9). As far post-traumatic stress disorder (PTSD), Loss Spectrum-Self Report (TALS-SR), as triggers are concerned, several po- post-traumatic stress spectrum, for the post-traumatic stress spectrum tentially precipitating factors (such as autism spectrum disorder, autistic symptomatology, the Adult Autism Sub- physical and psychological stressors) traits, chronic pain threshold spectrum (AdAS spectrum) have been called into question, albeit for the assessment of subthreshold au- without unequivocal conclusions (10, tism spectrum. The scores reported to 11). This notwithstanding, literature AdAS (total and per domain) by the en- has progressively recognised the rele- tire sample and subgroups with PTSD vance of traumatic or major life stress- diagnosis, partial PTSD and no PTSD ful events in triggering FM manifesta- were compared in order to detect a re- tions in vulnerable subjects, and hence lation between Autistic Traits (ATs) and the existence of a relationship between post-traumatic spectrum in this clinical FM and trauma-related disorders, in sample. particular Post-traumatic Stress Disor- Results. Our results show that FM pa- der (PTSD) (12, 13). tients with PTSD report an AdAS total PTSD is a highly prevalent psychiatric score significantly higher than those condition (14-17), whose onset follows Competing interests: none declared. reported by patients without PTSD. direct or indirect exposure to one or

S-20 Clinical and Experimental Rheumatology 2021 Adult Subthreshold spectrum correlates to PTSD spectrum in FM / C. Carmassi et al. more traumatic events and is character- and higher ATs, suggesting that children neurologic disease, seizures, stroke, or ised by an heterogeneous clinical pic- with mild ATs may become somatisa- head injury resulting in prolonged loss ture, tendency to a chronic course, poor tion-prone adults (35-38). Although the of consciousness and/or neurological response to treatments and relevant rate relation between FM and SSD is con- sequelae in the previous three months. of somatic symptoms (18) and medi- troversial, this finding is still of interest The study was conducted in accord- cal comorbidities (i.e. cardiovascular since SSD – whose main features are ance with the Declaration of Helsinki , metabolic disorders, autoim- the presence of somatic symptoms and and approved by the Ethics Committee mune diseases) (19, 20). Indeed, PTSD concerns about them - is at the same of the Area Vasta Nord Ovest Toscana, and trauma exposure history were re- time a common differential diagnosis Pisa, Italy. lated to the onset of various somatic and a misdiagnosis of FM (39-41), as a diseases as well as chronic pain condi- well as a relatively common comorbidi- Assessment tions (18, 21-24). In particular, several ty in FM patients (39). In addition, peo- A trained clinician (CA) collected researches demonstrate that PTSD is a ple with ASD show a peculiar pattern socio-demographic data of the sam- psychiatric disorder commonly occur- of sensory responses, which is charac- ple, such as marital status, employ- ing in FM patients, with comorbidity terised by hypo- or hypersensitivity to ment, educational level. Participants rates as high as 45.5% (25, 26), and sensory stimuli, including pain (42-45). also fulfilled two self-reported instru- that PTSD has a detrimental prognostic This issue is of interest considering ments: the Adult Autism Subthreshold significance in this clinical population, that the multisensory hypersensitivity spectrum (AdAS Spectrum) in order even in subthreshold forms (27, 28). has been investigated in several stud- to investigate autistic traits; the Trau- In addition, anamnestic evidence of a ies concerning the FM physiopathology ma And Loss Spectrum Self-Report traumatic exposure is common in FM (46-49) and an abnormal functioning (TALS-SR) to examine Post-traumatic patients with a significant prepoder- of brain areas involved in processing Stress spectrum symptoms. ance of the so-called interpersonal and of sensory and painful stimuli has been The AdAS is a self-reported question- network events (28). hypothesised as the underlying neural naire constituted by 160 dichotomous Interestingly, the finding of previous substrate of the so-called “pain centrali- items, developed in order to explore traumatic events and the high preva- sation” (50-55). typical and atypical symptoms or per- lence of PTSD are shared features be- Despite the suggestive findings on the sonological traits which can be referred tween FM and patients with Autism complex relationship between ATs, to the autistic spectrum. It should be Spectrum Disorder (ASD) or subthresh- PTSD and pain or somatic symptoms, emphasised that this psychometric old autistic traits (ATs) (29). ASD, as there is still a lack of data on this is- instrument follows a dimensional ap- defined by DSM-5, is a neurodevel- sue in FM patients. In this study we proach and has no diagnostic purpose opmental disorder whose key features explored the presence of ATs and PTSS as to ASD diagnosis (57). The items are impairment in social interaction in a sample of FM subjects in order are grouped in seven domains explor- and communication and repetitive be- to examine the possible relationship ing respectively childhood and adoles- haviors. Beyond the DSM diagnostic between these psychopathological di- cence (I), verbal communication (II), boundaries, previous studies have been mensions. non-verbal communication (III), em- demonstrating that ATs are dimension- pathy (IV), inflexibility and routinarity ally distributed in the general popula- Material and methods (V), restricted interests and ruminations tion, and that they are more pronounced Study sample (VI) and hypo-hyperreactivity to stim- among relatives of patients with ASD A sample of 119 patients was enrolled uli (VII). The AdAS Spectrum demon- and patients suffering from other psy- in the Reumathology Unit of Azien- strated excellent internal consistency chiatric conditions, such as PTSD (30, da Ospedaliera Universitaria Pisana for the total score as well as for five 31). In this framework, growing evi- (A.O.U.P, Pisa, Italy). Eligible subjects out of seven domains and found test- dence has been demonstrating a strong included patients of age between 18 retest reliability (ICC= .976). Subjects link between Post-traumatic Stress and 77 years diagnosed with FM ac- with ASD reported significantly higher spectrum symptoms and ASD, show- cording to the 2010 diagnostic criteria AdAS Spectrum total scores than both ing a high prevalence of Post-traumatic of the American College of Rheuma- patients with feed and spectrum symptoms or PTSD in sub- tology (ACR) (56). A psychiatric as- and healthy controls (57). jects with pronounced ATs (32-34). sessment was performed for each pa- The TALS-SR includes 116 dichoto- However, the relationship between FM tient by psychiatrists of the Psychiatric mous items exploring the lifetime ex- and adult autism spectrum is to date still Unit of the A.O.U.P. Exclusion criteria perience of a range of loss and/or trau- unexplored, although this issue may be included the lack of knowledge of the matic events and lifetime symptoms, worth of attention in the light of some Italian language or other limits to ver- behaviors and personal characteristics findings. Studies conducted on paediat- bal communication, poor capacity of that might represent manifestations and/ ric population suffering from Somatic collaboration or inability to provide or risk factors for the development of a Symptoms Disorder (SSD) revealed a informed consent, the documented stress response syndrome. The items correlation between somatic symptoms mental retardation or IQ<70, history of are grouped into nine domains, and do-

Clinical and Experimental Rheumatology 2021 S-21 Adult Subthreshold spectrum correlates to PTSD spectrum in FM / C. Carmassi et al.

Table I. Socio-demographic characteristics of the study sample (119 patients). characteristics in our sample we calcu- lated the mean and the standard devia- Age (years) mean ± SD 48.33 ± 11.63 tion (SD) for the quantitative variables. Conversely, frequencies and percent- n (%) ages were used to describe categorical data. Marital status Single 35; 29.9% Married or partnered 52; 44.5% The comparison of the AdAS Spectrum Separated/divorced 22;18.8% domains and total scores between dif- Widowed 8; 6.8% ferent groups constitued by patients Occupation Student 2;3.3% with PTSD, partial PTSD and without Unemployed 6; 9.8% PTSD was performed by means of one- Housewife 15; 24.6% way variance analysis (ANOVA). The Employed 33; 73.8% Retired 5; 8.2% post-hoc multiple comparisons were carried out with the t-test of Bonferroni Educational level Primary School 3; 4.9% Secondary school 19; 31.1% or with the Games-Howell test, respec- High school diploma 31; 50.8% tively, if the variance was equal or not Univeristy degree 5;8.2% equal, according to the test of homoge- Post graduate degree 2; 3.3% neity of variances. The relationship be- Development disorders Language 3; 3% tween AdAS and TALS-SR score was Movement 6; 5.9% examined through Pearson coefficient. The data were analysed using the Sta- main scores are obtained by counting Criterion B (B1=80; B2=77; B3=79; tistical Package for the Social Sciences the number of positive answers. The B4=78; B5=81). (OSSO). All tests were two-tailed and nine domains explored by the TALS- Criterion C (C1=86; C2=87 and/or 88 a p value <.05 was considered statisti- SR are: loss events (I); grief reactions and/or 89). cally significant. (II); potentially traumatic events (III); Criterion D (D1=90; D2=95; D3=85; reactions to losses or upsetting events D4=96; D5=91; D6=93; D7=92). Results (IV); re-experiencing (V); avoidance Criterion E (E1=108; E2=99 and/or The study sample was constituted by and numbing (VI); maladaptive cop- 100 and/or 102 and/or 103 and/or 104; 106 females (89%), 13 males (10.9%), ing (VII); arousal (VIII); and personal E3=106; E4=107; E5=105; E6=109). the mean age was 48.33±11.63 years. characteristics/risk factors (IX). In its Criteria proposed by previous studies Socio-demographic characteristics are validation study, TALS-SR demon- were adopted to assess the presence summarised in Table I. A total of 108 strated excellent validity and reliability of partial PTSD, that was the endorse- patients completed both the AdAS and as to the PTSD diagnosis (58). ment of two or three DSM-5 symptoms TALS-SR lifetime questionnaires. According to previous studies, the pres- cluster. This procedure allowed us The TALS-SR analysis showed that 40 ence of PTSD was assessed by means to divide the sample in three groups: patients (33.6%) met a PTSD diagno- of TALS-SR items endorsed corre- subjects with PTSD, partial PTSD and sis, while 40 (33.6%) reported a partial sponding to DSM-5 criteria for PTSD without PTSD ones. PTSD one. It is notewhorty that the diagnosis (59, 60). Specifically, we uti- percentage of patients reporting at least lised the following matching between Statistical analysis a partial PTSD was as high as 67.2% symptom criteria and TALS-SR items: To describe clinical and demographical (n=80) of the total sample (n=119).

Table II. Comparison between the AdAS total and domain score in the overall sample (108 patients) and by subgroup without PTSD (group a), with partial PTSD (group b) and with a PTSD diagnosis (group c).

AdAS Spectrum Domains FM patients FM patients FM patients FM patients F(2,105), p p<0.05 (n=108) without PTSD with Partial with PTSD mean ± SD (n=39) PTSD (n=35) (n=34) mean ± SD mean ± SD mean ± SD

I. Childhood/adolescence 4.83 ± 3.4 3.10 ± 1.99 5.00 ± 3.50 6.64 ± 3.69 11.804, <0.001 c,b>a II. Verbal Communication 4.36 ± 2.75 3.23 ± 2.25 4.45 ± 2.52 5.55 ± 3.02 7.294, 0.001 c>a III. Non-Verbal Communication 6.12 ± 3.79 3.51 ± 2.71 8.35 ± 3.73 8.35 ± 3.73 22.022, <0.001 c>a IV. Empathy 3.45 ± 2.64 3.25 ± 2.67 3.48 ± 2.36 3.64 ± 2.92 0.199, 0.820 - V. Inflexibility and adherence to routine 10.74 ± 6.3 7.57 ± 4.37 11.91 ± 6.69 13.14 ± 6.45 9.154, <0.001 c>a VI. Restricted interest and rumination 5.42 ± 4.05 3.28 ± 2.6 6.02 ± 4.05 7.26 ± 4.39 11.066, <0.001 c>a VII. Hyper-and hyporeactivity to sensory input 5.42 ± 4.05 3.02 ± 2.19 4.65 ± 3.54 5.91 ± 3.44 8.033, 0.001 c,b>a Total score 39.4 ± 19.92 27.00 ± 13.14 42.42 ± 18.79 50.52 ± 20.12 17,302 <0.001 c,b>a

S-22 Clinical and Experimental Rheumatology 2021 Adult Subthreshold spectrum correlates to PTSD spectrum in FM / C. Carmassi et al.

Table III. Correlations between total score and single domains score of TALS-SR and AdAS spectrum total and domain scores in the study sample (n=108).

TALS-SR

Loss events Reactions to loss Potentially Reactions to Re-experiencing Avoidance Maladaptive Arousal Risk Total r,p r,p traumatic to loss and r,p and numbing behaviours r,p factors r,p events trauma r,p r,p r,p r,p r,p

I. Childohood and 0.187 0.285* 0.392* 0.380* 0.374* 0.476** 0.416** 0.419** 0.272 0.465 adolescence 0.053 0.003 0.000 0.000 0.000 0.000 0.000 0.000 0.004 0.000

II. Verbal 0.118 0.312* 0.358* 0.406** 0.351* 0.402** 0.331* 0.426** 0.338* 0.451** communication 0.225 0.001 0.000 0.000 0.000 0.000 0.009 0.000 0.000 0.000

III. Non-verbal 0.188 0.413** 0.560** 0.539** 0.577** 0.572** 0.530** 0.591** 0.436** 0.643*** A communication 0.051 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

d IV. Empathy 0.233* 0.055 0.204* 0.049 0.119 0.112 0.143 0.143 0.193 0.157 0.015 0.575 0.034 0.616 0.220 0.248 0.139 0.139 0.045 0.106 A V. Routinarity and 0.103 0.427** 0.411** 0.459** 0.434** 0.452** 0.535** 0.535** 0.269* 0.536** S inflexibility 0.289 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.005 0.000

VI. Restricted interests 0 .051 0.439** 0.400* 0.459** 0.450** 0.487** 0.471** 0.459** 0.329* 0.526** and ruminations 0.603 0.000 0.000 0.000 0.002 0.000 0.000 0.000 0.001 0.000

VII. Hypo/Hyperreac- 0.036 0.277 0.442** 0.400* 0.398* 0.396* 0.462** 0.437** 0.246* 0.466** tivity to stimuli 0.783 0.004 0.000 0.000 0.000 0.000 0.000 0.000 0.010 0.000

Total 0.180 0.448** 0.535** 0.535** 0.533** 0.568** 0.509** 0.603*** 0.395* 0.639*** 0.062 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

*weak to moderate correlation; **moderate to strong correlation; ***strong correlation.

In the one way ANOVA, FM patients evidence of a positive relation between symptomatological overlap between diagnosed with PTSD had a significant the scores reported at the AdAS and PTSD and FM does not weaken in it- higher AdAS Spectrum total score with the presence of PTSD in FM patients self the validity and clinical relevance respect to without ones, besides a sig- sheds further light on the clinical and of the two distinct diagnosis, provided nificant higher score in all AdAS- do pathophysiological interface between that the corresponding diagnostic cri- mains, except for the empathy one (IV). these clinical entities. On one hand, teria are met. Hence, the PTSD preva- Patients with partial PTSD, reported it is aknowledged that ASD and ATs lence rate in our sample, that is in line intermediary results with respect to the are not only associated to a greater with literature (25, 26), may be con- other two groups, showing a significant traumatic exposure (61) but also rep- sidered as a further argument in favour difference only in AdAS Spectrum do- resent a vulnerable substrate for the of the high comorbidity rate between mains childhood/adolescence (I), and development of posttraumatic stress these two clinical conditions. It is hypo-hyper reactivity to stimuli (VIII), symptoms in the aftermath of a trauma also noteworthy that the analysis of beside AdAS Spectrum total score if (26). On the other hand, several stud- the TALS-SR domain scores showed, compared with FM patients without ies demonstrated the high prevalence consistently with literature (66-69), a PTSD (Table II). of full-blown or subthreeshold PTSD high prevalence of previous traumatic Finally, the Pearson correlations be- among FM patients and the relevance experiences with a significant prepon- tween the AdAS Spectrum and TALS of this comorbidity in adversely af- derance of interpersonal loss events domains enlighted the existence of a fecting the clinical picture of FM (27, and other relational trauma events. positive association between several 28, 62, 63). In this proposal, when However, to date no study has exam- domains of the two scales (Table III). examining these results, we may take ined the presence of autistic subthresh- into account the possible impact of a old symptoms and their relation with Discussion symptomatological overlap of FM and PTSD diagnosis in a clinical sample of To the best of our knowledge, this is some PTSD symptoms. In particu- FM patients. the first study exporing the relation- lar, symptoms such as restlessness, Our result enlighted significantly high- ship between subthreshold adult au- sleeping and concentration problems er AdAS Spectrum score in the group tistic spectrum symptoms and PTSD and hyper-vigilance are commonly with PTSD in respect to the group con- or Post-traumatic Stress spectrum observed in both conditions (64, 65). stitued by patients who did not meet symptoms, in patients with FM. The This notwithstanding, in our view the a PTSD diagnosis, with a significant

Clinical and Experimental Rheumatology 2021 S-23 Adult Subthreshold spectrum correlates to PTSD spectrum in FM / C. Carmassi et al. gap in all AdAS Spectrum domains the clinical burden of somatic symp- ing symptoms which are not FM relat- except the VIth (empathy). The group toms in post-traumatic stress pathol- ed (91). It has been hypothesised that diagnosed with partial PTSD was in an ogy has been increasingly recognised, over-reporting and central augmenta- intermediate position, with significant- with recent studies focusing on medical tion may either coexist in the same pa- ly higher values in the overall AdAS comorbidities and on the presence of tient or either may prevail in different Spectrum score in respect to the group multiple somatic complaints in PTSD patients (91, 92). In this regard, how- of patients without PTSD. In addition, a patients such as chronic pain, headache ever, it is worth noticing that in our comparison between the average AdAS and gastrointestinal disorder (75-79). In sample only the subsample of FM pa- Spectrum scores of this sample and that this regard, the underlying mechanisms tients with PTSD reported significantly reported by the control group of AdAS are still debated, since the interplay be- higher AdAS Spectrum score, this Spectrum validation study (57) provide tween hypotalamic-pituitary-adrenal suggesting that in this sample the high further insights: while no significant (HPA) axis alterations, proflogistic di- score was not attributable to FM per differences emerged between the en- athesis, and opioidergic system impair- se. Other limitations are represented by tire sample of FM patients and control ment outlines a complex physio-patho- the dishomogeneity of gender groups; group, the PTSD group showed higher logical scenario (80-85). In this frame- the use of self-reported instruments, score in all AdAS domains. work, the correlation between AdAS such as AdAS Spectrum and TALS- These results suggest that ATs may play Spectrum score and PTSD diagnosis SR; the lifetime structure of TALS-SR a role in shaping clinical manifesta- and that between AdAS and TALS-SR assessment, which does not allow us to tions of PTSD, thereby resulting in an domains in this cluster of patients - who examine the temporal relationship be- increased vulnerability to development suffer, by definition, of multidistrict tween the onset of the conditions under of somatic symptoms, such as pain pain – may suggest that subthreshold investigation. Finally, our research did symptoms or other functional disorder. autistic symptoms confer a combined not gather data on medical and psychi- On one hand, this hypothesis could be vulnerability to Post-traumatic Stress atric comorbidities in the sample. supported by literature evidence con- spectrum development and to somatisa- cerning the presence of neurodevel- tion in response to psychological and/ Conclusion opmental disorder and higher ATs in or physical stressors. This hypothesis is The results emerging from this study paediatric patients with SDD, whose strengthened by the resulting relation- confirm on one hand the high - comor potential meaning has been indicated in ship between the score reported in do- bidity rate between PTSD and FM, and the introduction (35-41). In this regard, main VII of the AdAS, which explores on the other hand the existence of a a potential underpinning pathophysio- hypo-hyperreactivity to stimuli. relevant relation between this associa- logical diathesis may consist in the doc- In addition, two further findings are tion and the presence of higher autistic umented alteration of sensory response worth mentioning: a moderate associa- symptoms in this cluster of patients. In to stimuli. Indeed, hyper-reactivity to tion between the score reported in the this framework, the analysis of the cor- sensory stimuli is one of the several ATs verbal comunication domain and the relations between AdAS Spectrum and explored by the AdAS Spectrum ques- total TALS-SR score and a strong asso- TALS-SR score leads to hypotesise a tionnaire (e.g. items 150 and 153) and ciation between the latter and the non- particular relevance of the hypo-hyper at the same time well-known clinical verbal communication domain score. sensitivity to stimuli and of deficit in features of FM (10, 49). This overlap- This finding is in line with previous verbal and non-verbal comunication in ping feature, along with the results of literature focusing on the association explaining this finding. Further studies the present study, may in our opinion of alexithimia (i.e. multidimensional are warranted in order to confirm this encourage further researches aimed to psychological construct that describes correlation, to detangle its directionality examine this issue. Moreover, while the a difficulty in cognitive processing of and to examine underlying psychologi- multisensory hypersensitivity and pain emotional experience leading to impair- cal and/or neurobiological mechanisms. centralisation have been conceptualised ment in communicating feelings and in as the aetiopathogenetic core features of emotional regulation) and pain sever- References FM (50, 51, 70, 71), other mechanisms ity in both FM and ASD patients (63, 1. JONES GT, ATZENI F, BEASLEY M, FLÜSS E, SARZI-PUTTINI P, MACFARLANE GJ: The (such as the disregulation of opioidergic 86-90). 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