Ciro Manzo

Drug-induced lupus erythematosus associated with donepezil: a case report

The possibility that drug-induced lupus erythematosus (DILE) can be induced by donepezil is presented in this clinical case. Donepezil is an inhibitor of acetylcholinesterase used for the treatment of Alzheimers disease. It is the first time that donepezil causes DILE.

Polymyalgia rheumatica with normal values of both erythrocyte sedimentation rate and C-reactive protein concentration at the time of diagnosis: a four-point guidance

Raised values of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration are typical findings in patients with polymyalgia rheumatica (PMR) at the time of diagnosis. In 1979 Bird et al. proposed an ESR of 40 mm/h or higher as a diagnostic criterion, and in 1981 Jones and Hazleman considered a CRP concentration of more than 6 mg/l as an additional criterion. In a sizable proportion of PMR patients – from 7% to 22% – ESR is not raised at the time of diagnosis. However, in these patients, CRP is usually raised [1]. The normal values of both of these biomarkers at the time of diagnosis were rarely reported. Myklebust and Gran [2] found normal both ESR and CRP in 1.2% of 178 PMR patients, and only one patient amongst 177 had normal ESR and normal CRP in a prospective follow-up study conducted in two Italian secondary referral centres of rheumatology [3]. In our medical records (data unpublished), six amongst 265 PMR patients had normal values of both ESR and CRP at diagnosis. The vast majority of these patients had no constitutional manifestations. The reasons why this can be possible in an auto-inflammatory disease are only speculative. The absence of constitutional manifestations could realise a first-favouring element. PMR with low ESR is considered a more benign form of disease, with lower frequency of constitutional manifestations compared to PMR with high ESR [4]. Innate immunity may trigger fever, general malaise, fatigue, and depressive reaction. In patients with PMR, their absence can be a result of interactions between innate and adaptive immunity within a specific genetic background [5]. Some speculated that PMR might be an incomplete form of giant cell arteritis (GCA), manifested in the regions in the proximity of axillary, subclavian, and/or femoral arteritis. A biopsy-proven GCA can be present without elevation of ESR and CRP [6], and in the literature GCA with normal ESR and CRP at diagnosis is much more frequent than PMR with normal values of inflammatory markers. Accordingly, it might be hypothesised that PMR patients with normal values of both ESR and CRP have an occult GCA. In individuals aged 50 years or older, in the presence of: persistent pain involving shoulders, pelvic girdle, and/or neck plus morning stiffness lasting for more than 1 hour plus absence of other different diseases (with the exception of giant cell arteritis), the diagnosis of PMR is possible. The rapid response (seven days, on average) to low-dosed prednisone (< 20 mg per day), together with watchful observation to ensure that no alternative diagnosis appear during follow-up, can confirm the first diagnosis. However in the clinical practice we must take into account that several patients fail to achieve a complete response after one week, and – on the other hand – some diseases can mimic PMR not only in the clinical features but also in a fast response to low-dosed systemic glucocorticoids. Some of these diseases fail to maintain the first positive response in a short time (with reappearance of manifestations despite glucocorticoid therapy) but others (such as solid or haematological tumours) can do it [7]. In recent years, ultrasound (US) imaging has become an integral element of the diagnostic process in PMR. Even if there are no pathognomonic findings, subdeltoid

Diagnosis of polymyalgia rheumatica in primary health care: favoring and confounding factors – a cohort study

Objectives To evaluate in a primary care setting the favoring and confounding factors for the diagnosis of polymyalgia rheumatica (PMR). Material and methods Among 303 patients consecutively referred by their general practitioners (GPs) to our rheumatologic outpatient clinic, we identified three groups: group A – patients with confirmed diagnosis of PMR, group B – patients with unconfirmed diagnosis, group C – patients with unrecognized PMR. All the diagnostic confounding and favoring factors were discussed with GPs using an e-mail questionnaire. Participation in rheumatology training courses represented the final question. The collected data were statistically assessed in a blind way. In Fisher’s exact test and ANOVA test, a p-value was significant if < 0.05. The study was carried out in compliance with the Helsinki Declaration and approved by the Ethics Committee of Mariano Lauro Hospital. Every patient signed an informed consent form at the time of the first visit. Results All patients were Caucasian; 24.1% were male; mean age was 72.3 ±8.6 years (min. – 51, max. – 94). There were 41 patients in group A, 93 in group B and 169 in group C. The percentage of misdiagnoses was very high (87.1%): among 134 patients diagnosed with PMR by their GPs (group A + group B) confirmation was made in 41, and in 169 unrecognized PMR was found. Participation in training courses was very significant compared to the diagnostic accuracy (p < 0.0001 in χ2 test) and to the diagnosis timing (24.3 days ±12.5 vs. 42.9 ±15.5 with p-value < 0.05 in the ANOVA test). When the percentages were assessed according to participation, an inadequate evaluation of some clinical manifestations favored over-diagnosis among the trained GPs. Conclusions The level of diagnostic accuracy for PMR must be improved in primary care. Participation in rheumatology training courses can be an important step.

Psychomotor Agitation Following Treatment with Hydroxychloroquine.

We describe the case of an elderly woman with elderly-onset rheumatoid arthritis, where the use of 4 mg/kg/day of hydroxychloroquine (HCQ) was followed by the onset of psychomotor agitation with marked physical and verbal violence towards her partner, including throwing objects at her partner. No disturbance in sleep and no anxiety, nervousness, or irritability had emerged before the onset of her psychomotor agitation. The disappearance of agitation following targeted pharmacologic intervention and HCQ interruption, its re-onset after reintroduction of the drug, and the high score (9) of Naranjo’s algorithm are surely linked to the existence of a causal relationship between HCQ and psychomotor agitation. HCQ may produce undesirable effects on the central nervous system, mainly irritability, nervousness, emotional changes, and nightmares. To the best of our knowledge, there are only a few case reports of psychosis due to HCQ. No favoring condition such as pharmacokinetic interactions or a personal and family psychiatric history was present in our patient. The neuropsychiatric manifestations we observed could be considered a bizarre-type adverse drug reaction linked to an individual’s hypersensitivity.

Behavioral, Psychiatric, and Cognitive Adverse Events in Older Persons Treated with Glucocorticoids

Background: Since the introduction of glucocorticoids (GCs) in the physician’s pharmacological arsenal, it has been known that they are a cause of behavioral or psychiatric adverse events (BPAE), as well as of cognitive problems. To the best of our knowledge, the relationship between these adverse events and GCs in older persons has never been evaluated, except through case-reports or series with few cases. In this paper, a review of the literature regarding BPAEs and cognitive disorders in older people treated with CSs is undertaken. Methods: A comprehensive literature search for BPAEs was carried out on the three main bibliographic databases: EMBASE, MEDLINE and PsycINFO (NICE HDAS interface). Emtree terms were: Steroid, steroid therapy, mental disease, mania, delirium, agitation, depression, behavior change, dementia, major cognitive impairment, elderly. The search was restricted to all clinical studies and case reports with focus on the aged (65+ years) published in any language since 1998. Results: Data on the prevalence of the various BPAEs in older patients treated with GCs were very scarse, consisting mainly of case reports and of series with small numbers of patients. It was hence not possible to perform any statistical evaluation of the data (including meta-analysis). Amongst BPAEs, he possibility that delirium can be induced by GCs has been recently been questioned. Co-morbidities and polypharmacy were additional risk factors for BPAEs in older persons. Conclusions: Data on BPAEs in older persons treated with GCs, have several unmet needs that need to be further evaluated with appropriately designed studies.

Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article

Little is known about the development of psychosis during hydroxychloroquine (HCQ) treatment, especially in elderly patients affected by rheumatic diseases, with multiple comorbidities and treatments. To summarize the available evidence on HCQ-induced psychosis in elders, we performed a literature review. Additionally, individual case safety reports sent to the European Pharmacovigilance database (EudraVigilance) with HCQ as suspected drug and related to adverse events belonging to the System Organ Class ‘Psychiatric disorders’ were shown. Over the years, evidence was published about the risk of neuropsychiatric clinical manifestations during HCQ treatment for rheumatic diseases, but few of them were related to elderly patients. These adverse events can include less severe clinical manifestations such as affect lability and nervousness or more severe conditions such as actual psychosis and suicidal tendencies, which frequency are actually unknown. The presence of risk factors in these patients may precipitate HCQ-induced psychosis and their precocious detection could be associated with a risk minimization. Among predisposing risk factors, there are the co-exposure to interacting drugs, alcohol intake, familial history of psychiatric diseases, female gender, and the concomitant use of low-dose glucocorticoids. In some cases it was possible to reverse psychotic behaviour with the antipsychotic treatment or with HCQ suspension.

Is primary Sjögren’s syndrome a risk factor for malignancies different from lymphomas? What does the literature highlight about it?

Background Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease with an elevated risk of developing lymphoproliferative malignancies (LM). Whether pSS is a risk factor or not for non-lymphoma malignancies (NLM) has been scarcely evaluated in the literature. Age is per se a risk factor for malignancies: patients over 70 years old have 4 times higher risk for cancers than adults. Even if the mean age of pSS onset usually is in the 4th and 5th decade, its onset in patients aged over 65 years (Elderly Onset pSS – EOpSS) is not uncommon. Material and methods To evaluate pSS as a risk factor for NLM we performed a systematic electronic search on PubMed in the period 2006–2016 to identify all the publications on this topic. The studies were eligible for inclusion if they reported specific Standardized Incidence Ratio (SIR) with 95% CI. Studies that did not report sufficient published and/or original data were excluded. Results Only 7 articles of 494 that we found in PubMed fulfilled the inclusion criterion. In the vast majority of these, SIR values were not statistically significant for NLM. The occurrence of NLM after LM was statistically significant in some studies and a NLM represented the most frequent cause of death. The possibility that NLM may represent a paraneoplastic syndrome seems much more frequent than LM, the risk of which increases with time after the diagnosis. Data regarding the neoplastic weight of EOpSS are mainly pointed out by case reports. Conclusions Primary Sjögren’s syndrome is not associated with an increased risk for NLM. However the possibility that NLM may appear after recovery from lymphoma should be carefully considered because it could be cause of the patient’s death. Similarly the possibility that NLM may represent a paraneoplastic syndrome must be highlighted. The relationship between EOpSS and SIRs for NLM should be deepened with studies on ad hoc cohorts.

Relapse of polymyalgia rheumatica after a fall

Approximately half of PMR patients have a relapse with a necessity to increase GC dosages. The role of external factors in inducing PMR relapse have been poorly investigated. We present a case-series of five PMR patients in remission with low doses of glucocorticosteroids (GC), who presented with relapse immediately after a fall. The assessment of PMR relapse was made using PMR-AS by Leeb and Bird, and a score > 9.35 was consistent with diagnosis of relapse. Gender, age, and cumulative dose of GC at the time of the fall were compared between the group of these five patients and a group of 41 PMR patients who had no PMR relapse after a fall: using the Fischer’s exact test a significant difference was pointed out when the p-value was < 0.05. In our five PMR patients, the sharp worsening of clinical manifestations was always accompanied by a significant rise of the inflammatory indices and the increase of GC dosage (almost always 10 mg/day of prednisone) prompted a fast return (seven days as average) to the previous clinical and laboratory features. All other potentially responsible factors were excluded. Several months (6–10 months on average) after the fall, none of these five patients had a new relapse. No significant differences were found when we compared age, sex, and the cumulative dose of GC at the time of the fall between the group of patients with PMR relapse and the group of patients without. The possibility of PMR relapse being realised immediately after a fall should be kept in mind in daily practice, especially when typical manifestations reappear immediately after a fall and other diagnostic hypotheses have been carefully excluded. The lack of important data (genetic factors, hormonal dosages, serum levels of IL-6 and/or serum soluble IL-6 receptor) in our case-series represented important limits for clarifying the nature of our observations and should be included in any subsequent study design on this argument. If our monocentric data are confirmed by multicentric data, the assessment of the risk of falls through specific scales should be an integral part of the visit of all PMR patients.

Polymyalgia Rheumatica in Association with Remitting Seronegative Sinovitis with Pitting Edema: a Neoplastic Warning

Polymyalgia rheumatica (PMR) is considered the commonest inflammatory rheumatological disease in adults aged greater than 65 years.(1-3) Classic symptoms are bilateral pain, aching and stiffness in the shoulders, pelvic girdle and neck, usually with sudden onset. In most cases the patient remembers the exact day when these symptoms appeared.(4,5) As opposed to the symptoms of osteoarthritis, the stiffness and pain tend to be bilateral or symmetric and improve with activity. They are greater in the morning and improve during the day. The dramatic response to low-dose corticosteroid treatment (15 mg/day prednisone or prednisone equivalent, on average) is characteristic and represents an important diagnostic criterion, despite the recent classification criteria proposed by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) collaborative group.(6) In some patients, it is necessary to change the initially used glucocorticoid with a different one at equivalent dosage to obtain an effective response.(4) The management of PMR is generally possible in a rheumatologic outpatient clinic without hospitalization.(7,8) The relationship between PMR and cancer is still uncertain, and the data available in the literature are contradictory. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is an uncommon elderly-onset rheumatic condition, described for the first time by McCarty et al.(9) in 1985. RS3PE syndrome is characterized by tenosynovitis of extensor tendons at the wrist and (less frequently) at the feet that characteristically respond to low-dosages of corticosteroids. Its removal occurs rapidly and relapse is extremely rare in the “benign” forms.(10,11) Since 1985, cancer and benign tumors have been described in association with RS3PE. RS3PE can represent a neoplastic marker in elderly patients with rheumatic diseases in up to 20% of cases.(12) The levels of vascular endothelial growth factor (VEGF), a cytokine able to increase vascular permeability and dilation, are significantly higher in RS3PE patients than in controls, and the levels decreased after glucocorticoid treatment.(13) The importance of VEGF in the neoplastic spreading is well-known,(14) but the real importance of VEGF in the paraneoplastic potentiality of RS3PE remains speculative until today. RS3PE can be an initial manifestation of PMR or may occur in its course. It is estimated that no more than 10% of patients with PMR may have an RS3PE syndrome, and some authors think that RS3PE can be considered an integral part of the spectrum of the PMR manifestations.(15) We have evaluated 200 elderly patients (> 65 years old) with PMR, consecutively observed at our rheumatologic outpatient clinic from 2002 to 2014, with regard to presence/absence of RS3PE and presence/absence of a paraneoplastic syndrome. The diagnosis of PMR was made, until 2013, using the criteria proposed by Healey(16) and, after 2013, using the criteria proposed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).(6) The minimum observation time for the appearance of an eventual cancer has been of 24 months from initial diagnosis of PMR. The lack of response to corticosteroid therapy and/or the appearance of signs or symptoms not consistent with typical PMR have shown to be warns for finding eventual cancer. In the same cohort of patients, the presence of RS3PE syndrome was highlighted in a binary way (yes / no): the fact that the RS3PE is a manifestation of onset or appears during the course of PMR in addition to other clinical manifestations did not constitute an element of assessment. The occurrence of cancer was compared between patients with PMR without RS3PE and those with PMR + RS3PE. The presence of RS3PE was observed in only seven patients with PMR (3.5%). In three of the seven patients with RS3PE associated with PMR (5 M, 2 F) it was possible to recognize a tumor: prostatic cancer, vescical cancer, multiple myeloma (Table 1). In all these patients, RS3PE presented before the discovery of the malignancies. Its reappearance after a short while represented in all three cases an element of strong suspicion. Subsequent diagnostic decisions were indicated by specific signs: significant rise of prostate specific antigen or appearance of hematuria or a monoclonal peak at Polymyalgia Rheumatica in Association with Remitting Seronegative Sinovitis with Pitting Edema: a Neoplastic Warning

[Relationship between 25-hydroxy vitamin D and cognitive status in older adults: the COGNIDAGE study].

AIM The aim of the COGNIDAGE study was to examine the association between 25(OH)D and cognitive status in a group of elderly patients with vitamin D deficiency and high burden of comorbidities attending Geriatric Outpatient Clinics. MATERIALS AND METHODS We studied the relationship between 25(OH)D and cognitive functions taking into account comorbidities and cognitive functions assessed by MMSE (Mini Mental State Examination), CDT (Clock Drawing Test) and CIRS (Cumulative Illness Rating Scale), in 132 consecutive elderly patients with low levels of 25(OH)D (<10 ng/ml) compatible with the condition of vitamin deficiency. The association among 25(OH)D levels, MMSE score, CDT score and CIRS scores were analyzed using Pearson correlation. All the elderly patients received an adequate vitamin D supplementation and were reassessed after 6 months. RESULTS At baseline, mean MMSE and CIRS scores were: 21.8+5.56 and 2.96 +1.63 respectively. Mean CDT score was 3,66+-2.05. No associations were found between 25(OH)D levels and global cognitive function. A significant relationship was observed between the total CIRS score and 25(OH)D levels (r=0.305; p=0.000) as well as between total CIRS score and MMSE (r=-0.375; p=0.000). After 6 months, 83.9 % had 25(OH)D levels >20 ng/ml. Mean MMSE and CDT scores were 22.20+-5.76 and 3.90+-2.06 respectively. There was no significant correlation among 25(OH)D, MMSE and CDT scores while a significant correlation was found between 25(OH)D and CIRS- severity score (r=0.275; p=0.001) and between MMSE and total CIRS scores (r=-0.247; p=0.005 for CIRS-comorbidities; r=-0.184; p=0.04 for CIRS-severity). A post hoc evaluation on two subgroups of elderly patients (the first with vitamin D deficiency without cognitive impairment, the second with vitamin D deficiency and dementia) showed a statistically significant difference (p=0.00001) regarding the CIRS-comorbidities scores. CONCLUSIONS In our cohort of elderly patients with a high burden of comorbidities, 25(OH)D low levels (<10 ng/ml) are not associated with MMSE and CDT scores. There is no statistically difference among the levels of 25(OH)D and MMSE and CDT scores after 6 months. The strong correlation we found regarding CIRS-comorbidities in the two sub-groups suggests that vitamin D deficiency may play a role in promoting cognitive impairment only with comorbidities.