Efficacy of Monotherapy with Biologics and JAK Inhibitors for the Treatment of Rheumatoid Arthritis: A Systematic Review

Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE^®, Embase^®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010–2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA.Funding: Pfizer.Plain Language Summary: Plain language summary available on the journal website.     

Expanding role of AMPK in endocrinology.

Adenosine 5' monophosphate-activated protein kinase (AMPK) is a regulator of cellular and systemic energy homeostasis. It mediates some of the effects of peripheral hormones such as leptin, ghrelin and adiponectin, and it is involved in the insulin-sensitizing role of the antidiabetic drug metformin. There is increasing evidence that AMPK has a central role in mediating the appetite-modulating and metabolic effects of many other hormones and substances, including the cannabinoids. Recent studies have illustrated the interaction between hormones and AMPK, and highlighted AMPK as a potential target for the development of tissue-specific AMPK modulators in the treatment of obesity and the metabolic syndrome.     

Surgical extrusion: A dental technique

This article describes a technique for surgically extruding severely compromised roots needing prosthetic rehabilitation. Unlike previously described approaches, the technique does not require advanced clinical skills or equipment, may reduce the risk of tooth or bone fracture during the luxation maneuvers, and does not seem to interfere with the alveolar socket healing process.     

The value of the low-dose dexamethasone suppression test in the differential diagnosis of hyperandrogenism in women

We studied 211 hyperandrogenic women with respect to clinical presentation, basal androgen levels, and the degree of cortisol and androgen suppression during a 48-h low-dose (2 mg) dexamethasone-suppression test (LDDST) to exclude ovarian and adrenal tumors. In 42 women with elevated testosterone levels, 21 of whom failed to suppress testosterone during the LDDST, the response of serum androgen levels during a 4-wk administration of 7.5 mg prednisolone in a reverse circadian regimen was also assessed. These results were compared with an additional 17 patients with histologically proven androgen-secreting tumors. Clinical presentation alone was suggestive of a virilizing tumor in 70% of patients with tumors. Serum testosterone, although occasionally only marginally elevated, was the sole androgen that was elevated in every patient with a tumor. After the LDDST, none of the patients with tumors obtained either a greater than 40% reduction or normalization of the previously elevated testosterone levels, whereas 88% of patients with nontumorous hyperandrogenism showed either normalization or suppression of more than 40%. With one exception, all of the patients with nontumorous hyperandrogenism who showed inadequate suppression of testosterone during the LDDST, and were treated with prednisolone, normalized the previously elevated androgens after 1 month of administration. In summary, in women presenting with hyperandrogenism, lack of testosterone suppression during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting tumors from patients with nontumorous hyperandrogenism in this small series. The LDDST is an easy to perform screening test that can also identify causes of hyperandrogenism due to altered glucocorticoid secretion.     

Functional and nonfunctional adrenocortical tumors demonstrate a high responsiveness to low-dose adrenocorticotropin

Aldosterone-producing adenomas (APAs) demonstrate exquisite sensitivity to endogenous ACTH. We previously showed an ACTH receptor overexpression in APAs compared with the other adrenal tumors. To evaluate the meaning of such findings, we investigated the response of aldosterone, cortisol, and 17OH progesterone (17OHP) to 1 microg ACTH in 42 patients with adrenocortical tumors (23 NHAs, 9 APAs, and 10 CPAs) and 10 normal subjects (C). All 52 subjects were responsive to ACTH, and hormone peak levels were reached at 30 min. The aldosterone peak level was significantly higher in APAs [mean +/- SEM: 84.3 +/- 13.1 ng/dl (2335.1 +/- 362.9 pmol/liter)] than in other tumors and control (C). Cortisol peak levels was higher in CPAs [37.1 +/- 3.9 microg/dl (1023.9 +/- 107.6 nmol/liter)] than in NHAs (P < 0.01), in C (P < 0.01) and in APAs (P = n.s.). 17OHP peak levels were significantly higher in patients with adrenocortical tumors toward C. In summary: 1) low-dose ACTH induces an important stimulation in all tumors, suggesting preservation of high responsiveness to ACTH; 2) this is especially true for aldosterone in APA and could be of primary importance when performing diagnostic tests for hyperaldosteronism; and 3) 17OHP-hyperresponsiveness to low-dose ACTH is the most common alteration both in functional and nonfunctional tumors.     

Reduced expression of the growth hormone and type 1 insulin-like growth factor receptors in human somatotroph tumours and an analysis of possible mutations of the growth hormone receptor

OBJECTIVE: Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours. METHODS: We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene. RESULTS: No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P < 0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P < 0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P < 0.01). CONCLUSIONS: Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.     

Implant Patient Compliance Varies by Periodontal Treatment History

Background: This retrospective study aims to assess compliance to supportive periodontal therapy (SPT) among patients treated with dental implants with different periodontitis histories and the possible influence of their compliance on peri‐implant marginal bone level. Methods: Dental records of 106 patients treated with at least one dental implant were reviewed. A single operator who did not provide care to the patients recorded the following during the first year of implant function (first year of follow‐up), during the first 5 years of follow‐up, and during the entire follow‐up duration: 1) number of recalls; 2) compliance, calculated from registered attendance; 3) periodontal disease history; 4) peri‐implant radiographic bone level from most recent examination; and 5) clinical parameters including probing depth and bleeding on probing. Clinical and radiographic parameters were assessed at site level and analyzed for possible associations among them and with demographic parameters. Results: Collected data were based on 156 implants with an average of 6.5 ± 3.4 years (range: 1 to 13 years) in function. Patients with periodontitis history demonstrated greater compliance than patients without periodontitis history during the two longer follow‐up times. Over time, the majority of patients demonstrated partial compliance (71% to 80% of patients). Peri‐implant bone level averaged 0.9 ± 1.1 mm, without significant association with compliance level; however, positive periodontitis history and more years in function were significantly associated with greater peri‐implant bone loss. Conclusions: Patients with implants partially comply with scheduled SPT, regardless of periodontitis history. Patients who had received periodontal treatment demonstrated better compliance than those without prior periodontal therapy experiences.