The effect of risankizumab on achieving minimal clinically important differences in patient-reported outcomes in patients with psoriatic arthritis: results from KEEPsAKE 1 and 2.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease that reduces the quality of life. This study assessed the effects of risankizumab (RZB) on the achievement of minimal clinically important differences (MCID) in patient-reported outcomes (PROs). METHODS: KEEPsAKE-1 and -2 are randomized, placebo-controlled Phase 3 clinical studies assessing RZB (150 mg) vs. placebo (PBO) in adult patients with PsA with inadequate response or intolerance to disease-modifying antirheumatic drugs and/or biologics. Patients were randomized 1:1 to receive RZB or PBO for 24 weeks; starting at Week 24, all patients received RZB 150 mg through Week 52. PROs assessed were Patient's Global Assessment of Disease Activity (PtGA), Patient's Assessment of Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Short-Form 36 Physical and Mental Component Summary scores (PCS and MCS, respectively), 5-Level EQ-5D (EQ-5D-5L), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment (WPAI). The proportion of patients achieving MCID at Weeks 24 and 52 are reported. Odds ratios of achieving MCID with RZB treatment at Week 24, relative to PBO, were estimated by logistic regression controlling for baseline and stratification factors. RESULTS: In KEEPsAKE-1, RZB- vs. PBO-treated patients were more likely to report MCID in all PROs at Week 24; similar results were obtained in KEEPsAKE-2, except for SF-36 MCS and WPAI presenteeism domain. In KEEPsAKE-1 and KEEPsAKE-2, 65% and 62% of RZB-treated patients, respectively, reported MCID in PtGA at Week 24, which increased to 74% and 68%, respectively, at Week 52. Approximately 48% of all PBO-treated patients reported MCID in PtGA at Week 24 and, after initiating RZB, >65% reported MCID at Week 52. Results were similar in the remaining PROs. CONCLUSIONS: These data demonstrate that patients with PsA receiving RZB treatment are more likely to report clinically important improvements in PROs compared with patients receiving PBO.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study.

OBJECTIVES: To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. METHODS: SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)-erythrocyte sedimentation rate (ESR) over 6 months. RESULTS: 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3-ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3-ESR at 6 months was significantly greater in rituximab than TNFi patients: -1.5 (0.2) vs -1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (-1.7 vs -1.3; p=0.017) but not intolerance (-0.7 vs -0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3-ESR with rituximab than with TNFi (-1.6 (0.3) vs -1.2 (0.3); p=0.011), particularly those switching because of inefficacy (-1.9 (0.3) vs -1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. CONCLUSIONS: These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Assessment of anti-TNF-alpha efficacy in rheumatoid arthritis: is 3 months sufficient?

OBJECTIVES: The optimal therapeutic trial duration of anti-TNF-alpha therapy is currently unknown. The British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of treatment and recommends not to persist beyond 6 months. The National Institute for Health and Clinical Excellence (NICE) specifies treatment continuation if response is achieved by 6 months, yet the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) maintain a 3 month cut-off. No evidence exists to support a 6 month therapeutic trial over 3 months. Thus, we undertook a study to evaluate the proportion of patients who failed to meet NICE response criteria at 3 months but obtained this by 6 months, and to identify predictive factors for this. METHODS: Patients who commenced anti-TNF-alpha therapy for RA were studied, counting those who switched to a second or third agent separately for each instigation of therapy (n = 244). Response at 3 and 6 months was defined according to NICE criteria as a >or=1.2 reduction in Disease Activity Score (DAS28). RESULTS: Of the 189 patients with available 3 month DAS28 responses, 149 fulfilled response criteria. Of the 40 who failed, 27 continued treatment, of whom 21 were available for follow-up at 6 months. Out of the 21 patients, 12 (57%; 95% CI 36, 78) achieved a response at this time. This data set was too small to investigate predictors of response at 6 months. CONCLUSIONS: A substantial proportion of patients who fail NICE response criteria at 3 months and continue on treatment to 6 months achieve a response. These results support a 6 month therapeutic trial over 3 months.

Hypovitaminosis D among rheumatology outpatients in clinical practice.

OBJECTIVES: A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients. METHODS: Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores. RESULTS: A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D. CONCLUSIONS: Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Malignant mesonephric neoplasms of the uterine cervix. A report of eight cases, including four with a malignant spindle cell component.

Eight mesonephric adenocarcinomas of the uterine cervix, four of which had a malignant spindle-cell component, occurred in women aged 34 to 71 (median 43, mean 54.5) years, bringing to 14 the number of cervical mesonephric carcinomas in the literature. The tumors with a malignant spindle-cell component ("malignant mesonephric mixed tumors") are, with one possible exception, the first reported examples at this site. The patients, almost all of whom presented with vaginal bleeding, underwent hysterectomy; five also had a pelvic lymph node dissection. The tumors were all stage IB, although microscopic lymph node metastases were found in two cases. Gross examination revealed an invasive cervical mass in each case. On microscopic examination, seven tumors were adjacent to mesonephric hyperplasia, which in five cases was florid and focally atypical; in the remaining case, occasional non-neoplastic mesonephric tubules were found only within the tumor. The adenocarcinomas typically exhibited a variety of patterns, including a ductal pattern resembling endometrioid adenocarcinoma, a small tubular pattern, a retiform pattern, a solid pattern, and a sex-cord-like pattern. These disparate patterns frequently caused diagnostic difficulty. The spindle-cell component generally resembled endometrial stromal sarcoma or a nonspecific spindle-cell sarcoma; one tumor also contained multiple foci of osteosarcoma and another, a single chondroid focus. Immunohistochemical staining for a variety of antigens failed to reveal a distinctive profile, although all the carcinomas were immunoreactive for vimentin. Follow-up in six cases revealed three patients to be alive without evidence of recurrence at postoperative intervals of 2 to 3 years. Recurrent tumor developed in a fourth patient 1 year after hysterectomy; she was treated with chemotherapy and was alive and free of disease at 2 years. Another patient had intra-abdominal recurrences (including liver metastases) at 9 and 11 years and was alive with tumor at 13 years. Death at 8.5 months in a final patient was probably due to an independent stage IIc ovarian clear-cell carcinoma. These and prior observations in the literature suggest that malignant mesonephric tumors of the cervix may be more indolent than their müllerian counterparts, from which they should be distinguished. Mesonephric carcinomas in this site should also be distinguished from florid mesonephric hyperplasia, with which they are usually associated.

Congenital cystic adenomatoid malformation of the lung.

Ten cases of congenital cystic adenomatoid malformation of the lung are presented, together with a review of the literature. Two infants were stillborn; the others died shortly after birth. Eight had hydrops, and in eight the pregnancy was complicated by hydramnios. Grossly, one or two lobes of the lung were affected, the remaining lobe(s) and the opposite lung being hypoplastic. The lesions were solid, or cystic. Apart from a solitary cutaneous hamartoma, there was no associated anomaly. Microscopically, two patterns were seen--solid and mixed. "Mucigenic epithelium" was seen in six cases. The pathogenesis of this lesion, together with that of the hydrops and hydramnios, is discussed. It is concluded that congenital cystic adenomatoid malformation of the lung is a distinct pathological entity; its prompt recognition and surgical correction should result in normal survival.

Ceroid granulomas in the female genital system.

Three cases of ceroid granulomas of the female genital system are presented, involving the cervix in two and lesions in the ovaries and bowel serosa in the other. Ceroid granulomas are unusual and interesting lesions formed when suitable substrates accumulate within macrophages to such an extent that a relative lack of biological antioxidants results and auto-oxidation and conversion to ceroid is favoured. This may occur in the setting of haemorrhage and necrosis, whether from tumour necrosis or associated with endometriosis. Other sources of lipids and lipoproteins include bile, meconium and vernix caseosa.

Microinvasive adenocarcinoma of the cervix: a clinicopathologic study of 77 women.

OBJECTIVE: To prove that microinvasive adenocarcinoma of the cervix exists and, like its squamous counterpart, carries an excellent prognosis. METHODS: Seventy-seven women with microinvasive adenocarcinoma of the cervix were seen from 1971 to 1995. Microinvasion was defined as depth of invasion or tumor thickness of at most 5 mm. Microscopic assessment was made on punch biopsies, serially sectioned conization specimens, and extensively sampled hysterectomy specimens. RESULTS: Most of the women had abnormal Papanicolaou smears. We made definitive diagnoses on conization specimens in 49 women, hysterectomy specimens in 22, and colposcopically directed punch biopsies in six (three being no residual disease in the subsequent conization-hysterectomy specimens). The length of microinvasive adenocarcinomas ranged from 0.8 to 21 mm, and the volume was between 3 and 1000 mm. The tumors were multicentric in 21 cases, but no true "skip" lesions were found. Overall, 58 cold-knife conizations were performed: the margins were free in 39 cases, involved in 18, and inconclusive in one. The one loop conization had involved margins. Definitive therapy included cold-knife conization in 16 women, combined with pelvic-node dissection in four. In the remainder of the women, we performed some type of hysterectomy. None of the 26 women who had radical hysterectomy had parametrial spread, and none of the 48 who had pelvic-node dissection or the 23 in whom one or both adnexa were removed had metastases. There have been two "recurrences" to date; one was an adenocarcinoma and the other a squamous cell carcinoma, both at the vault. CONCLUSION: Microinvasive adenocarcinoma of the cervix is a clinicopathologic entity that appears to have the same prognosis, and should be treated in the same way, as its squamous counterpart.

Site and origin of squamous cervical cancer: a histomorphologic study.

Based on extensive histomorphologic study, a concept of cervical carcinogenesis is formulated. Intraepithelial neoplasia arises in well defined and predestined fields that are well demarcated from each other. Different forms of intraepithelial neoplasia coexist and have different topographic distribution. Extension and enlargement of atypical epithelial fields are not brought about by active spread, but by apposition of new fields. Two different pathways exist for the genesis of intraepithelial neoplasia affecting cell types involved in regeneration or transformation. In the majority of cases the precursor lesion is atypical squamous metaplasia in the transformation zone. Less commonly, malignant change occurs in original squamous epithelium, probably via atypical basal hyperplasia. The role of the "last gland" is seen as the anatomic landmark dividing these two areas. So-called minor forms of intraepithelial neoplasia cannot progress and change into carcinoma in situ, as they are differently located.

Angiomyxomas of the umbilical cord.

Rare benign angiomyxomatous tumors of the umbilical cord, associated with a macerated stillbirth, are described. Only 12 cases of vascular tumor of the cord have been reported and only 2 of these were associated with fetal death. The histopathology of this unusual tumor is presented together with a review of the literature.

Arteriovenous malformations of the uterus.

Six cases of the rare condition of arteriovenous malformation of the uterus are reported. Uterine bleeding was the most common presentation, with the site of the lesion and the caliber of the vessels determining its degree. A preoperative diagnosis was made by angiography in two patients, and was aided by ultrasonography in one.

Ovarian mucinous tumour with a focus of anaplastic carcinoma: a case report.

A 50-yr-old patient presented with abdominal symptoms due to the presence of cystic ovarian tumours. After hysterectomy and bilateral salpingo-oophorectomy, the diagnosis of a mucinous tumour with a focus of anaplastic carcinoma in one ovary and a dermoid cyst in the other was made. Further treatment was refused and the patient died 12 mth after operation with disseminated anaplastic carcinoma. The case is the first reported when adjuvant therapy has not been given and illustrates the poor natural history of this disease.

Collision tumor: serous adenocarcinoma and steroid cell tumor of the ovary.

A "collision" tumor between a serous papillary adenocarcinoma and a steroid cell tumor of the ovary is described. No similar combination has been reported in the literature. The steroid cell component secreted testosterone, resulted in considerable virilization of the patient, and appears to have preceded the carcinoma by several years. It remains problematical whether the androgenic milieu may have predisposed to the development of the second, malignant, tumor.

Bilateral pulmonary agenesis.

Two cases of bilateral pulmonary agenesis in infants of 31 and 41 weeks gestation are reported. In addition to absence of both lungs, major abnormalities not previously reported were also found in other systems. It is concluded that these abnormalities are not due to chromosomal abnormality but no alternative can be offered.

Alpha-fetoprotein-producing adenocarcinoma of the sigmoid colon with possible hepatoid differentiation.

A patient with adenocarcinoma of the sigmoid colon producing alpha-fetoprotein (AFP) is described. Hepatoid differentiation is suggested by the morphological appearance and production of hepatic-type AFP. The possible histogenesis of such a tumor is discussed.

Survey of congenital tumors in perinatal necropsies.

In an audit of 17,417 necropsies from 1939 to 1989 at the Royal Women's Hospital, Melbourne, Victoria, 46 congenital tumors comprising 24 teratomas, 8 vascular tumors, 6 neuroblastomas, three rhabdomyomas, two mesoblastic nephromas, one thyroid adenoma, one hepatic adenoma and one cerebellar medulloblastoma were found. The teratomas were generally large tumors and, because of their size and location, incompatible with extrauterine life. Ten teratomas were associated with polyhydramnios, three with obstructed labour, five of the fetuses were hydropic and four had malformations at sites distant to the tumor. Twenty teratomas occurred in stillbirths, half of whom were macerated. The vascular tumors were associated with polyhydramnios in three cases and hydrops fetalis in two. The neuroblastomas were all incidental findings. Four were intra-adrenal, one was an adrenal tumor which had metastasized to the liver and the remaining case was a small paravertebral lesion. Two of the three rhabdomyomas were multiple and one of these occurred in a case of tuberous sclerosis. One of the mesoblastic nephromas occurred in a hydropic fetus who had the Arnold-Chiari malformation. The thyroid and hepatic adenomas were small incidental lesions. The cerebellar medulloblastoma had led to marked hydrocephalus. Congenital tumors have different incidence, presentation and behaviour than those in childhood or adult life. The association of congenital tumors with congenital malformations and hydrops fetalis should always be remembered.

Diagnosis of cervical epithelial abnormalities from 'routine' uterine curettings.

Fragments of cervical tissue are frequently found in uterine curettings. These may consist of endocervical mucosa, squamous epithelium, or both. To determine the frequency of abnormalities in this epithelium, 4000 consecutive endometrial curettings were examined during the year ending December 1977. Abnormal squamous epithelium was found in 20 cases (0.5%). The abnormalities were defined for the purpose of the study to include dysplasia/carcinoma in situ and warty atypia. Cases in which endometrial curettage was performed during the work-up for known dysplasia or carcinoma in situ were excluded. Subsequent follow-up included cytology, colposcopy, and colposcopically-directed target biopsies; occasionally conization and hysterectomy were performed. The most significant abnormality detected in this way was carcinoma in situ with early stromal invasion. The definitive treatment in most cases was cervical diathermy. As the abnormalities in the initial scrapings were previously unsuspected, it is imperative for the anatomic pathologist to look for and carefully evaluate cervical fragments in all endometrial curettings.

The accuracy and interobserver reproducibility of endometrial dating.

Although controversial, diagnosis of luteal phase defect (LPD) includes the morphological assessment of endometrial development. This study was conducted to determine if refresher training in the histological criteria could improve the accuracy and interobserver reproducibility of endometrial dating. Seventy-eight endometrial biopsies were dated by a reference panel of two pathologists and then reviewed twice by a study panel of four pathologists. In the first review, usual practice was applied. Prior to the second review, they studied a standard document of histological criteria. Samples were dated as proliferative, secretory (post-ovulatory day, POD), menstrual, and undatable. Accuracy levels based on the reference dating and agreement levels using kappa values were calculated per review and compared. The kappa for overall dating was 0.683 in the first review and 0.696 in the second. The respective first and second review kappa values were 0.736 and 0.771 for proliferative, and 0.794 and 0.764 for secretory. Amongst those dated as secretory in the first and second reviews, respectively, 31 and 28% were assigned the same POD by any two panellists, 68 and 63% were dated to within 1 day, and 77 and 71% were dated to within 2 days. Accuracy levels per panellist for overall dating were very high in both reviews but were low for individual PODs. Accuracy and interobserver reproducibility were unaffected by refresher training, suggesting the limits of histological dating have been reached.

Rectal adenocarcinoma with germ cell elements treated with chemotherapy.

A patient with adenocarcinoma of the rectum containing germ cell elements in the form of endodermal sinus tumor and choriocarcinoma is described, believed to be the first such tumor reported in the literature. The serum levels of alpha-fetoprotein and human chorionic gonadotropin were markedly elevated. The source of the markers was localized to the neoplastic tissue by the immunoperoxidase technique. The patient developed extensive hepatic metastases thought to be due to choriocarcinoma for which she received chemotherapy. One wk after commencing treatment a massive fatal hepatic hemorrhage occurred.