Anti-tumor necrosis factor α: originators versus biosimilars, comparison in clinical response assessment in a multicenter cohort of patients with inflammatory arthropathies.

OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.

Efficacy of a gluten-free diet in reducing the widespread pain index and symptom severity scale in patients affected by fibromyalgia.

OBJECTIVE: Dietary interventions to improve fibromyalgia (FM) symptoms reported conflicting results. This study aimed to treat FM patients with a gluten-free diet (GFD), alternated with a non-restricted gluten-containing diet, followed by a rechallenge of the GFD. METHODS: Twenty postmenopausal women with FM and no history of celiac disease participated. A GFD was assigned for 6 months. This was followed by 3 months of a non-restricted gluten-containing diet and then a new GFD for another 6 months. At each visit, the widespread pain index (WPI) and the symptom severity scale (SS) scores were evaluated. RESULTS: The mean age of the patients enrolled was 53.9±10 years. None of the patients had a diagnosis of irritable bowel disease, although they reported vague gastrointestinal symptoms. After 6 months of a GFD, a statistically significant reduction was observed for the WPI (10.3±1.8 vs 7.7±1.4; p<0.0001) and the SS scale (6.4±1.8 vs 4.15±1.6; p=0.0002). The D percentage reduction of the WPI after 6 months of GFD was -24%±9%, while for the SS scale, it was -36%±21%. The following reintroduction of a gluten-containing diet brought about a statistically significant rise in the absolute SS scale and WPI, as well as a D modification of the WPI (21%±13%) and of the SS scale (74%±90%). The rechallenge of the GFD showed a significant improvement in absolute and D WPI (-24%±7%) and SS (-36%±11%). No modifications to the body mass index were found. CONCLUSIONS: A GFD improved FM symptoms evaluated with WPI and SS. This was confirmed for the first time, also with a rechallenge of the GFD that followed a non-restricted gluten-containing diet.

Biclonal gammopathy of undetermined significance in a patient with systemic lupus erythematosus and antiphospholipid syndrome.

The case of a patient suffering from systemic lupus erythematosus with associated antiphospholipid antibody syndrome is described. In this patient, on protein electrophoresis, two monoclonal immunoglobulin G λ and k peaks were seen, defining a condition of biclonal gammopathy of undetermined significance (BGUS). This condition is extremely rare, especially in chronic inflammatory rheumatic diseases. The criteria of a BGUS are defined. We also underline how this condition can be the expression of a concomitant unrecognized cancer, a possible amyloidosis or an infectious process.

Efficacy of gluten-free diet in patients with rheumatoid arthritis.

Recent research has increasingly shown that depending on the foods we eat, gut flora may be affected by an inflammatory or anti-inflammatory response, thus playing an important role in inflammatory autoimmune diseases, such as rheumatoid arthritis or gastroenterological disorders. Gluten seems to be a glycoprotein with a clinically relevant inflammatory effect. Several observational studies and anecdotal cases reported a correlation between gluten and various diseases, including autoimmune diseases, such as rheumatoid arthritis. This study aimed to evaluate whether gluten-free diet could be effective in controlling inflammation and ongoing rheumatoid arthritis symptoms. We report 4 cases of patients with long-standing rheumatoid arthritis with no response to several conventional and biotechnological drugs, treated with a gluten-free diet concurrently with the drug therapy. Our patients presented different degrees of response to the diet, in terms of disease remission and improvement of symptoms. Our cases confirm that a gluten-free diet may improve symptoms of rheumatoid arthritis, even in patients resistant to conventional drug therapies.

Psoriatic spondyloarthritis and Sjögren syndrome: a casual association?

The association between Sjögren syndrome (SS) and psoriatic arthritis (PsA) is rare. Herein, we report a case of SS in a PsA patient with the mutilans variant. A 67-year old woman developed PsA with progressive articular destruction up to the typical deformation of 'telescoping fingers' in the distal phalanges. Psoriatic onychopathy presented ten years after the osteolytic damage in the hands. This late appearance led to delayed diagnosis and therapy, and, consequently, worsened the articular destruction. Thereafter, the patient developed a typical SS with clinical symptoms, such as xerophthalmia and xerostomia. This diagnosis was confirmed by positive diagnostic tests, such as Schirmer test, ANA, and anti-SSA/Ro and anti-SSB/La antibodies. A potential association between the two diseases is discussed.

Spondylodiscitis (Andersson lesion) in psoriatic spondyloarthritis: a rare event successfully treated with an anti-TNF therapy.

Spondylodiscitis (Andersson lesion) is an infrequent and late complication of advanced ankilosing arthritis. Scanty data on the efficacy of anti-TNF therapy for these lesions are available. To our knowledge, only few cases of spondylodiscitis occurring in patients with psoriatic arthritis were reported in literature. We describe the case of a patient with psoriatic arthritis who early developed Andersson lesions successfully treated with infliximab plus methotrexate therapy.

Radiological outcomes in randomized controlled trials on biologic therapies for rheumatoid arthritis: a narrative review.

Several scores are currently used to estimate the radiologic progression of patients affected by rheumatoid arthritis. Modified Sharp score, Genant-modified Sharp score and van der Heijde-modified Sharp score are actually the most commonly used scores in randomized controlled trials on biologic drugs actually available in scientific literature. An intensive literature search (EMBASE, PubMed, MEDLINE) was performed in order to identify randomized controlled studies reporting on the efficacy of biologic drugs on radiologic progression in rheumatoid arthritis by means of approved scoring methods such as Sharp score variants. All studies were evaluated for their approach to radiologic outcome, and a global evaluation of trends towards radiologic evaluation was performed. Eighteen studies were identified and analyzed, and data from such randomized controlled trials (RCTs) were reported and described regarding their approach to radiologic outcomes. The use of three different scoring methodologies generated similar but non-comparable data; although a big part of the studies reported good efficacy profiles of several biologic drugs on radiologic progression, data from such studies are not comparable as the three different scoring methods are not convertible from one to another. At present, there is no standardization for the evaluation of radiologic outcomes, thus preventing comparison of results obtained by different drugs. The use of a single, standardized and widely approved scoring method would grant the possibility of comparing such data.

Therapeutic effectiveness of minimal doses of rituximab in a patient with rheumatoid arthritis.

We report the case of a man suffering from rheumatoid arthritis, resistant to common DMARDs and anti-TNF-alpha, who received an excellent response, in terms of effectiveness and depletion of CD20 positive B-lymphocytes, to minimal doses of anti-CD20 monoclonal antibody (rituximab). The dose used was only 100 mg, repeated after 2 weeks. Already after the first infusion of rituximab, a profound depletion of CD20 B-lymphocytes and an improvement of clinical symptoms were evident. The patient, after 4 months from the first two infusions, maintained an accentuated lymphocyte depletion and obtained a low disease activity, passing from an initial DAS28 of 6.3 to a DAS28 of 2.8. The possible practical implications of this observation are taken into consideration.

Spondylodiscitis as the only clinical manifestation of the onset of psoriatic spondyloarthritis.

We report the case of a 47-year-old man with insidious onset of progressively disabling back pain in the dorsal region. The patient had minimal dermatitic lesions to the elbows and behind the ears, which were attributed to minimal psoriasis. An initial MRI of the spine, one month after the onset of symptoms, showed an alteration in the D7-D8 vertebrae as from bone marrow edema. The successive CT scan of the spine, after about six months, showed a significant osteolytic process of the D7 and D8 vertebrae and extensive swelling of surrounding tissues. A contemporary lung CT scan showed opacity in the right lung. A first hypothesis of lung cancer with vertebral metastases was ruled out by the negative bronchoscopy and the subsequent disappearance of lung opacity after antibiotic therapy. A CT-guided needle biopsy of the spine gave negative results for granulomatous and infectious tumor pathology. The later appearance of peripheral polyarthritis and the presence of initial bone marrow edema justified the diagnosis of psoriatic spondylodiscitis. Therapy with anti-TNF-alpha (Eternacept) was initiated, with which both the painful symptomatology and the radiological damage were quickly resolved. This is the first case in literature about spondylodiscitis as the manifestation of the onset of psoriatic spondyloarthritis.

Rheumatoid arthritis: a complication of aromatase inhibitor therapy?

We report the case of a 56-year-old woman treated with aromatase inhibitors for a breast cancer. Following one year of such therapy, the patient presented with widespread osteoarthrealgia. The clinical picture worsened 3 years later when the pain became more severe with swelling and stiffness involving several joints in a symmetric fashion. Biochemical analysis showed an increase of ESR, CRP and rheumatoid factor, as well as of anti-CCP antibodies. The x-ray was compatible with a diagnosis of rheumatoid arthritis (RA). Therapy with methotrexate, prednisol one, bisphosphonates and vitamin D was started, achieving a quick clinical remission. Aromatase inhibitors have been shown to alter the distribution of Th1/Th2 lymphocytes and increase the level of RANKL. A possible role of aromatase inhibitors in RA development has been further addressed.

Efficacy of cyclosporine in the treatment of a case of infliximab-induced erythrodermic psoriasis.

A clinical case is described of infliximab-induced erythrodermic psoriasis resistant to conventional topical therapy and high-dose corticosteroids. Cyclosporine therapy for some months resolved the severe psoriasis picture. Pathogenetic mechanisms are considered through which anti-TNF agents could induce psoriasis. An activation of T lymphocytes with cutaneous overexpression of a CXCR3 subset and, mainly, an increase in IFN-alpha due to the blockage of TNF-alpha could be the causes for this paradoxical adverse event of biological agents. Cyclosporine can work in psoriasis induced by biological agents thanks to its peculiar suppressive activity on T lymphocytes and the concomitant specific action on keratocytes and angiogenesis.

Unexpected and persistent depletion of B lymphocytes CD20 following a minimum dose of anti-CD20 antibody (Rituximab).

This study describes a woman patient suffering from rheumatoid arthritis which was resistant to treatment with the most commonly used DMARDs and anti-TNF alfa drugs, however following the administration of a minimum dose of Rituximab the patient showed a persistent and complete depletion of CD 20 lymphocytes. The dose of Rituximab administered to the patient was halted at 50 mg due to the onset of an allergic reaction. Based on these observations, a number of important speculations are possible, which however would require a larger number of case histories for their confirmation.

[Diffused suberitrodermic psoriasis induced by infliximab]. / Psoriasi suberitrodermica diffusa indotta da infliximab.

The case of a young male is described, affected by Crohn disease with reactive Spondylarthritis essay with Infliximab to the dose of 3 mg/kgs. After 15 days from the third infusion, the patient developed a first psoriasis eruption to the palm of the hands and the plant of the feet, for which was begun topical therapy with cortisone. After an initial improvement, the patient suffered a diffusion of the psoriasis eruption to the whole trunk and the limbs with a suberitrodermic aspect. The possible pathogenesis of this paradoxical effect of the anti-TNF is considered. Also being still partly the causes, is important the inhibition of the TNF-alpha with consequent expansion of the INF-alpha, in turn potential inductor of psoriasis.

Asymptomatic multiple duodenal diverticulosis. A rare case report.

The authors report the case of a patient with an unusually high number of diverticular formations (at least five), distributed along the entire duodenal tract. Following a review of the literature on this subject, the authors focus on the lack of symptoms manifested by duodenal diverticula, even if they are numerous and large in size, and on the extremely rare reports of multiple diverticula, as in this case.

Induction of theophylline clearance by rifampin and rifabutin in healthy male volunteers.

Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy. However, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study, involving 12 adult male volunteers, compared the effects of 14-day courses of rifampin and rifabutin on clearance of theophylline, a substrate for the hepatic microsomal enzyme CYP1A2. Subjects were given oral theophylline solution (5 mg/kg of body weight) on day 1 and then randomized to receive daily rifampin (300 mg) or rifabutin (300 mg) on days 3 to 16. Theophylline was readministered as described above on day 15. The first treatment sequence was followed by a 2-week washout period; subjects then received the alternative treatment. Theophylline concentrations were determined for 46 h after each dose, and pharmacokinetic parameters were determined. One subject developed flu-like symptoms while taking rifabutin and withdrew voluntarily. Results from the remaining 11 subjects are reported. Compared with the baseline, the mean area under the concentration-time curve (AUC) (+/- standard deviation) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 micrograms . h/ml, P <0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/- 45 micrograms.h/ml). Baseline theophylline AUCs before each treatment phase were not different. A comparison of equal doses of rifampin and rifabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is significantly less following rifabutin treatment than it is following rifampin treatment. However, the relative induction potency for other metabolic enzymes remains to be investigated.

Molecular karyotyping of multiple yeast species isolated from nine patients with AIDS during prolonged fluconazole therapy.

Variations in molecular karyotype and fluconazole susceptibility of serial yeast isolates from the oral cavities of nine patients with AIDS receiving fluconazole for single or multiple episodes of oropharyngeal candidiasis were monitored. Multiple yeast species were isolated from the initial oral specimens in six patients. Molecular karyotyping identified at least eight different DNA subtypes of C. albicans, at least eight of T. glabrata and only one DNA subtype each of C. krusei, C. tropicalis and C. parapsilosis. Among isolates of T. glabrata, fluconazole MICs in each patient were consistently within one or two dilutions, regardless of strain variations. Similarly, among five patients monitored during one course of therapy, the MICs of fluconazole of C. albicans isolates of either the same or different DNA subtypes remained within two dilutions. However, increases in MICs of fluconazole of C. albicans were observed in four patients who received two or more courses of fluconazole, three of whom had the same DNA subtype and one of whom changed from one DNA subtype to another.

Effect of fluconazole on pharmacokinetics of 2',3'-dideoxyinosine in persons seropositive for human immunodeficiency virus.

Fluconazole inhibits cytochrome P-450-mediated enzymatic metabolism of several drugs. Since hepatic metabolism is partially responsible for 2',3'-dideoxyinosine (didanosine or ddI) elimination, fluconazole therapy may lead to increased ddI concentrations in serum and subsequent concentration-dependent adverse effects. The purpose of this study was to determine if ddI pharmacokinetics are influenced by a 7-day course of oral fluconazole. Twelve adults with human immunodeficiency virus (HIV) who had received a constant dosage of ddI for at least 2 weeks were investigated. On study day 1, multiple serum samples for determination of ddI concentrations were obtained over 12 h. Then subjects received a 7-day course of oral fluconazole (200 mg every 12 h for two doses and then 200 mg once daily for 6 days) while ddI therapy continued. Following the last dose of fluconazole, serum samples for determination of ddI concentrations were again obtained over 12 h. ddI concentrations in serum were analyzed by radioimmunoassay. In contrast to previously published data, there was marked between-subject variability in ddI areas under the concentration-time curve, even when the dose was normalized for weight. No significant differences were found between mean ddI areas under the concentration-time curve from 0 to 12 h on study day 1 (1,528 +/- 902 ngx.hr/ml) and following fluconazole treatment (1,486 +/- 649 ngx.hr/ml) . There were no significant differences in other pharmacokinetic parameters, such as ddI peak concentrations in serum (971 +/- 509 and 942 +/- 442 ng/ml) or half-lives (80 +/- 32 and 85 +/- 21 min.) before and after fluconazole treatment, respectively. We conclude that a 7-day course of oral fluconazole does not significantly alter ddI pharmacokinetics in adults that are infected with human immunodeficiency virus.

[Neoplastic pericarditis secondary to ovarian adenocarcinoma. Report of a clinical case]. / Pericardite neoplastica secondaria ad adenocarcinoma ovarico. Descrizione di un caso clinico.

The pericardial metastatic disease is rare in genital cancers but is frequent in all other cancer. The authors report the case of a female affected by both papillary ovarian cancer and pericardial metastatic disease. Carcinomatous pericarditis began with cardiac tamponade. This pericarditis is very rare during ovarian cancer and there is little informations in the literature about it. The clinical picture showed an acuteness that cleared up with many pericardial tapping paracenteses, and after six cycles of polychemotherapy we obtained the disappearance of pericardial effusion and metastasis with total disappearance of abdominal metastases and the total remission of the cancer.