Triva Case

A 61-Year-Old Man With Crampy Abdominal Pain

A 61-year-old white man presents to the emergency department with a 1-week history of diffuse "crampy" abdominal pain. For the past 2 months, he has had diarrhea and has been passing blood with every bowel movement, either on the stool surface or separately from the stool. Recently, he has had 10-15 loose stools per day, with associated urgency and tenesmus. He has lost 4 lb in the past week. He feels lightheaded upon standing and is experiencing fatigue and mild shortness of breath. He takes atorvastatin for hypercholesteremia and acetaminophen for intermittent back and knee pain. He is allergic to penicillin. He has no history of gastrointestinal tract disease; screening colonoscopy performed 2 years ago was unremarkable. His father died of myocardial infarction when he was in his 60s, and his mother died of breast cancer when she was in her 40s. He has no siblings. He is retired from his work as an accountant and lives with his wife. He has not travelled recently. He has a 25-pack-year smoking history but has not smoked for approximately 10 years. He drinks alcohol on social occasions and on weekends, and he denies illicit drug abuse.
On physical examination, the patient is a pale, diaphoretic man in some distress due to abdominal pain. His oral temperature is 101.5°F (38.6°C), blood pressure is 110/62 mm Hg, pulse is 107 beats/min, and respiratory rate is 24 breaths/min. His body mass index is 29.7 kg/m². Examination of his head and neck is unremarkable aside from pale mucosal membranes. Lung auscultation reveals normal breath sounds, with no crackles or rhonchi. His heart rate is tachycardic, and his heart rhythm is regular. There are no murmurs or extra heart sounds. His abdomen is distended and firm, with diffuse rebound tenderness that seems worse in the lower left quadrant. Bowel sounds are diminished. No hepatosplenomegaly, ascites, or palpable masses are appreciated. Digital rectal examination demonstrates normal rectal tone, "velvety" rectal mucosa, and bright red blood on withdrawal of the examining finger. There is pitting edema of the legs and feet.
Laboratory analysis includes a complete blood count (CBC), which demonstrates anemia (hemoglobin concentration of 6.7 g/dL [67 g/L]), leukocytosis (leukocyte count of 14.2 x 10³ cells/μL [14.2 x 10⁹ cells/L]), and thrombocytosis (platelet count of 540 x 10³ cells/µL [540 x 10⁹ cells/L]). Additional findings include elevations in the erythrocyte sedimentation rate (78 mm/h) and C-reactive protein level (114 mg/L). His albumin level is low, at 2.0 g/dL (20 g/L). The basic metabolic panel is unremarkable. Repeat stool cultures and samples for ova and parasites are negative. Flexible sigmoidoscopy shows diffusely erythematous and friable colonic mucosa with large ulcerated patches, abundant yellow-white exudate, and oozing blood. These findings extend in a proximal and continuous fashion from the rectum to at least the middle of the sigmoid colon. Tissue biopsy samples sent for histopathologic examination reveal lymphoplasmacytic inflammation along the base of the crypts; neutrophils that infiltrate the crypt epithelium and collect in the depths of the colonic crypts to form "crypt abscesses"; and focal chronic reactive changes, including crypt branching, gland atrophy, and goblet-cell mucin depletion. No granulomas are identified.

What is the most likely diagnosis?

Hint: Note the frequent passage of bloody loose stools for more than 2 months in the setting of fever, tachycardia, and anemia.


The diagnosis of fulminant ulcerative colitis, an idiopathic form of inflammatory bowel disease, was initially suspected on the basis of the patient's history, physical examination, and laboratory test results; endoscopic and biopsy findings confirmed the diagnosis. The rectal bleeding was bright red, indicating that the source of the bleeding was most likely the lower gastrointestinal tract. The concurrent presence of crampy abdominal pain, diarrhea, tenesmus, and fever suggested that an inflammatory process had damaged the colonic mucosa. The unremarkable colonoscopy findings 2 years before presentation rendered a neoplasm unlikely. Although not impossible, it is rare for colon cancer to present with diarrhea. Most compelling was the continuity and character of the mucosal damage identified on endoscopy and the histopathologic findings, which were diagnostic of ulcerative colitis. Symptom duration suggested a chronic inflammatory process and infectious causes of colitis had been ruled out.
Ulcerative colitis is estimated to respectively have an incidence of 7.3 and prevalence of 116 per 100,000 people in the United States.^[1] The peak age at onset is 15-25 years, with a second peak at 40-60 years.^[2] Individuals of Ashkenazi Jewish or Scandinavian descent are more often affected, with men and women experiencing a similar disease incidence. Smoking seems to play a protective role against the development of ulcerative colitis, and it has been proposed that the second incidence peak in part represents patients who stopped smoking at a later age.^[3] Most research suggests that the etiology and pathogenesis of ulcerative colitis are multifactorial, with a combination of genetic susceptibility, bacterial antigens, and alteration of mucosal immunity responsible for the development of the disease.^[4]
Histopathologically, ulcerative colitis is characterized by lymphoplasmacytic inflammation of the mucosa and submucosa, with scattered neutrophils in the lamina propria (Figure 1). The neutrophils typically injure the crypt epithelium and may collect in the base of the crypts, forming crypt abscesses (Figure 2). Within weeks of disease onset, features of crypt architectural distortion (such as crypt branching and shortening) develop; these chronic changes are a nonspecific regenerative response to previous injury. Deep granulomas and transmural inflammation, 2 hallmarks of Crohn's disease, do not occur.^[5]
Classically, ulcerative colitis is insidious in onset. Affected patients present with frequent passage of bloody, loose stools and tenesmus. The intensity of the symptoms generally correlates with the extent of anatomic involvement, allowing classification of disease as mild, moderate, or severe/fulminant. The majority of patients have mild, indolent disease limited to the rectum and sigmoid colon that is characterized by diarrhea, intermittent rectal bleeding, and tenesmus. The physical examination is often normal aside from bright red blood within the rectum. Other patients present with systemic symptoms, including more frequent bowel movements, crampy abdominal pain, decreased bowel sounds, high-grade fever, tachycardia, anemia, orthostatic hypotension, and weight loss. Extraintestinal manifestations, such as acute arthropathy, episcleritis, erythema nodosum, and pyoderma gangrenosum may also arise. Fewer than 10% of patients with ulcerative colitis initially present with fulminant disease, with older individuals represented in greater numbers. Fulminant ulcerative colitis is more abrupt in onset and is usually characterized by extensive colonic involvement ("pancolitis"), with rectal bleeding that may be extensive enough to necessitate blood transfusion. Abdominal distention and tenderness to palpation with signs of peritoneal inflammation (eg, rebound tenderness) may be observed in these patients. Of greatest concern in patients with fulminant disease is the prospect of massive hemorrhage, toxic megacolon, or bowel perforation. Immediate hospitalization is often necessary in these patients.
The differential diagnosis of bright red blood in the rectum associated with diarrhea includes infectious colitis, ischemic colitis, and nonsteroidal anti-inflammatory drug enteropathy. Other causes of colonic bleeding, such as diverticular disease, can present with loose stools, because blood is a cathartic. Stool studies (eg, fecal leukocytes, culture, ova, and parasites) and a Clostridium difficile toxin screen should be considered to eliminate the possibility of infectious colitis. A complete blood cell count should be obtained to evaluate for anemia or leukocytosis. Low albumin levels signify poor nutritional status and protein-losing enteropathy. A basic metabolic panel may demonstrate electrolyte abnormalities in the setting of severe prolonged diarrhea. Inflammatory markers, such as the erythrocyte sedimentation rate and C-reactive protein level, are typically elevated in patients with inflammatory bowel disease. Radiographic studies may be used as an adjunct in diagnosing complications of ulcerative colitis (eg, plain films can establish the presence of toxic megacolon). In the setting of acute flares, other radiologic studies, such as computed tomography (CT), may be done to evaluate for an alternative diagnosis. Common CT findings in ulcerative colitis include thickening of the colonic wall, pericolonic fat stranding, and a "target" appearance of the rectum. Most important in confirming the diagnosis of ulcerative colitis is flexible sigmoidoscopy with biopsy; colonoscopy may also be used in some settings, but it is associated with a higher risk for perforation and is contraindicated in cases of suspected toxic megacolon. Typical endoscopic findings in ulcerative colitis patients include diffuse erythema; edema; friability; and granularity of the mucosa, with loss of the normal vascular pattern. Ulceration with exudate and pseudopolyps are frequently identified as well. These findings invariably begin in the rectum and extend proximally in a continuous manner, up to and including the cecum, in cases of pancolitis.^[6]
In most cases, ulcerative colitis can be managed in the outpatient setting. Treatment is designed to achieve and maintain disease remission. Topical therapy and 5-aminosalicylic acid (ASA) agents are the first-line means of treating ulcerative colitis, with steroids for acute flares and immunomodulators as maintenance therapy in severe refractory disease. Fulminant ulcerative colitis requires careful attention to the development of toxic megacolon. Parenteral corticosteroids; rehydration; bowel rest; nutritional supplementation; anticoagulation with low-dose heparin to prevent venous thrombosis, which is common in patients with ulcerative colitis; and monitoring of hemoglobin values (with transfusion sometimes required) are recommended. If remission is achieved, a maintenance regimen consisting of immunomodulators (such as cyclosporine, 6-mercaptopurine, or azathioprine) and/or 5-ASA should be initiated. In patients with fulminant ulcerative colitis that is refractory to first-line therapy, infusion of a biologic agent (such as infliximab) or colectomy may be necessary.^[7]
The patient in this case was immediately admitted to the hospital because of concerns that he was at risk for massive hemorrhage, toxic megacolon, or bowel perforation. Three units of cross-matched blood were transfused, and he was prescribed bowel rest, peripheral hyperalimentation, and prednisolone. Shortly thereafter, 5-ASA was added to his therapeutic regimen. His symptoms resolved gradually, and he was discharged to home. Over the next few years, he experienced several disease flares, and the benefits and risks of immunomodulators and biologic agents versus colectomy were reviewed with him during a particularly severe flare. After considerable reflection, he decided in favor of colectomy; the patient tolerated the operation well. Gross examination of the colectomy specimen demonstrated involvement of the entire colon from cecum to anus. Multiple irregular ulcers with an associated yellow-white exudate were scattered throughout the colon, and diffuse pseudopolyps (Figure 3) were present. Findings consistent with Crohn's disease (eg, fissures, fistulas, perianal involvement, "creeping fat," and segmental disease) were not identified. As expected, the procedure resulted in complete remission of the patient's symptoms. After ileal pouch anal anastomosis surgery, most patients can expect to have 4-6 loose bowel movements per day.

Q1. You are caring for a patient with abdominal pain, fever, and hematochezia and are concerned that the patient has ulcerative colitis. Which finding is most consistent with a diagnosis of ulcerative colitis?

	Pseudopolyps	Correct Answer	41%
	Segmental disease ("skip lesions")		15%
	Perianal involvement		12%
	Transmural inflammation		25%
	Deep granulomas		7%

 Pseudopolyps are a common alteration of the colonic mucosa in patients with long-standing active ulcerative colitis; they are raised areas of inflamed, regenerative tissue arising in a background of ulceration. When present in significant numbers, pseudopolyps can cause cobblestoning of the mucosa that does not regress, even with treatment. Segmental disease ("skip lesions"), perianal involvement, transmural inflammation, and granulomas are all manifestations of Crohn's disease, another form of inflammatory bowel disease.

Q2. You are caring for a patient with known ulcerative colitis. Which of the following clinical manifestations is more worrisome for severe or fulminant ulcerative colitis?

	Hematochezia		31%
	Diarrhea		6%
	Sacroiliitis		7%
	High-grade fever	Correct Answer	50%
	Tenesmus		7%

Stroke Prevention Trial in Children With Sickle Cell Disease and Iron Overload Halted

Susan Jeffrey

June 9, 2010 — The National Heart, Lung and Blood Institute (NHLBI) announced it has stopped a clinical trial in children with sickle cell disease and iron overload because the newer treatment being evaluated, hydroxyurea with regular phlebotomy, was found to be unlikely to prevent recurrent strokes better than standard therapy combining blood transfusion with deferasirox.
The trial, called Stroke With Transfusions Changing to Hydroxyurea (SWiTCH), had enrolled 133 children from 26 US sites and was comparing the 2 treatment regimens.
"Protecting our participants is an important factor in determining whether to stop a trial," Susan B. Shurin, MD, acting director of the NHBLI, said in a statement from the National Institutes of Health (NIH) dated June 3. About one third of participants had completed the study, during which they were treated and monitored for about 30 months.
The study's Data and Safety Monitoring Board reviewed interim results from the trial and recommended halting the trial; the NHLBI accepted the recommendation and stopped the trial May 6, the statement notes. The board pointed out that no strokes occurred in 66 participants treated with blood transfusions and deferasirox, whereas 7 strokes occurred in the 67 children receiving hydroxyurea and phlebotomy.
Study participants and their families have been contacted and will discuss their future options with their healthcare providers, the NIH release notes.
Previous research has shown that hydroxyurea helps prevent pain crises and some lung complications in adults, and it is the only US Food and Drug Administration–approved drug for treating sickle cell anemia. Preliminary studies had suggested hydroxyurea may also reduce the risk for stroke recurrence in children.
The SWiTCH trial included children between 5 and 18 years of age, all of whom had had a previous stroke. All had been receiving standard therapy with blood transfusions for at least 18 months before enrolment, and all had high levels of iron. The study compared hydroxyurea with standard transfusion therapy and also compared 2 approaches to reduce the iron overload that results from transfusion therapy: phlebotomy, simple regular blood removal, and deferasirox, an iron chelation agent.
Preliminary findings showed phlebotomy did not reduce liver iron better than deferasirox, and analysis of the data available suggested continuing the trial was unlikely to show that phlebotomy would provide a greater benefit in controlling iron accumulation. "Without the ability to provide benefits for the management of liver iron, the potential risks of continuing study treatments were no longer warranted," the NIH statement notes.
The study was scheduled to run until 2012. Rho Inc, of Chapel Hill, North Carolina, served as the SWiTCH statistics and data management center. "Researchers will analyze and publish the final data in the coming months," the statement concludes.
The study was funded by the NHLBI. Novartis US donated the deferasirox (Exjade). Bristol-Myers Squibb and UPM Pharmaceuticals Inc provided the hydroxyurea for the trial.

Valproic Acid in Pregnancy Linked to Several Congenital Malformations

Megan Brooks

June 9, 2010 — A new study confirms that first-trimester exposure to valproic acid is associated with an increased risk for spina bifida compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.
The study also links first-trimester valproic acid exposure to increased risk for 5 other congenital malformations: atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis.
"It is well known that first trimester exposure to valproic acid is associated with increased risk of spina bifida, confirmed in this study. But data on the risks of other specific birth defects are limited," study investigator Lolkje T.W. de Jong-van den Berg, PhD, from the Department of Pharmacoepidemiology and Pharmacoeconomics, University of Groningen, the Netherlands, noted in an email to Medscape Neurology.
"The reason is that most studies are too small to evaluate the risk of other specific birth defects of which the prevalence is rare."
However, it should be recognized, the authors conclude, that although the relative risks for several malformations were increased in association with valproic acid use in early pregnancy, the absolute rates are low. The majority of children born to mothers who took valproic acid while pregnant do not have malformations, they write.
Their study was published in the June 10 issue of The New England Journal of Medicine.
For this report, Dr. de Jong-van den Berg and colleagues combined data from 8 published cohort studies, including a total of 1565 pregnancies during which women were exposed to valproic acid, among which 118 major malformations were found.
They found 14 malformations that were significantly (P < .05) more common among the offspring of women who had taken valproic acid during the first trimester. The investigators tested these associations by performing a case-control study within the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database.
Included in the analysis were 37,154 cases, defined as having at least 1 of the following 14 malformations: spina bifida, microcephaly, ventricular septal defect, atrial septal defect, tetralogy of Fallot, pulmonary valve atresia, hypoplastic right heart, cleft palate, diaphragmatic hernia, gastroschisis, hypospadias, clubfoot, polydactyly, and craniosynostosis. Also included were 39,472 control patients without chromosomal abnormalities (control group 1) and 11,763 control patients with chromosomal abnormalities (control group 2).
Exposure to valproic acid monotherapy was documented in 122 patients with malformations, 45 control group 1 participants, and 12 control group 2 patients. The frequency of exposure to valproic acid was 3 times as high among patients with malformations, at 3.3 per 1000 registrations — that is, pregnancy outcomes with malformations included in EUROCAT — as among control patients in both groups, where the frequency was 1.1 per 1000.
Key Findings
"We found an increased risk with valproic acid exposure for 6 of the 14 malformations," Dr. de Jong-van den Berg said. Risk for spina bifida was 12 to 16 times as high for exposed fetuses, depending on the control group used, and risks for the 5 other conditions were 2 to 7 times as high.
Risk for Malformations Associated With First-Trimester Valproic Acid Monotherapy vs No First Trimester Antiepileptic Drug (Control Group 1)

Condition	Adjusted Odds Ratios	95% Confidence Interval
Spina bifida	12.7	7.7 - 20.7
Atrial septal defect	2.5	1.4 - 4.4
Cleft palate	5.2	2.8 - 9.9
Hypospadias	4.8	2.9 - 8.1
Polydactyly	2.2	1.0 - 4.5
Craniosynostosis	6.8	1.8 - 18.8

The results were generally similar in analyses comparing case patients with the control participants in group 2. The researchers also found an association between limb defects and exposure to valproic acid monotherapy as compared with no antiepileptic drug exposure — a finding that has been seen in previous case-control studies, they note.
The risks for most of these malformations (5/6) remained significantly increased in analyses comparing exposure to valproic acid monotherapy with exposure to other antiepileptic drug monotherapy. This supports a "relationship of these malformations to valproic acid specifically rather than to antiepileptic drugs generally or to underlying epilepsy," the authors say.
Steer Clear When Possible; Planning Ahead Critical
Current guidelines from the American Academy of Neurology recommend avoiding valproic acid in pregnant women, if possible, because of the risk for major congenital malformations as well as poor cognitive outcomes.
"In my group, we steer away from [valproic acid] unless it is the only drug that works," Sandra L. Helmers, MD, MPH, who was not involved in the study, noted in a telephone interview with Medscape Neurology.
Because switching drugs during or just before pregnancy is difficult, a forward-thinking approach is important, she added.
"This new study again emphasizes how important this issue is in not only women who are pregnant but women of childbearing age. That means you have to plan ahead, from day 1 — that means teenage women with epilepsy — and discuss this with them," added Dr. Helmers, who is an associate professor of neurology and pediatrics at Emory University School of Medicine in Atlanta and a member of the American Academy of Neurology.
Dr. de Jong-van den Berg and coauthors and Dr. Helmers have disclosed no relevant financial relationships.
N Engl J Med. 2010;362:2185-2193.

Benefits of Erlotinib Maintenance in NSCLC: SATURN Results Published CME

News Author: Nick Mulcahy
CME Author: Charles Vega, MD

May 20, 2010 — Results from the phase 3 Sequential Tarceva in Unresectable NSCLC (SATURN) trial are now published online in The Lancet Oncology.
The results show that, compared with placebo, erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) maintenance therapy significantly improves progression-free survival (hazard ratio [HR], 0.71; median, 12.3 vs11.1 weeks) and overall survival (HR, 0.81; median, 12.0 vs 11.0 months) in patients with advanced nonsmall-cell lung cancer (NSCLC).
The data were first presented at the 2009 World Conference on Lung Cancer and reported by Medscape Oncology at the time.
The most dramatic outcomes with erlotinib were seen in a small subset of patients in the trial — those with an epidermal growth-factor receptor (EGFR) mutation — but these patients accounted for only 22 of the 438 (5%) erlotinib-treated patients.
"Erlotinib was associated with an unprecedented hazard ratio of 0.10 (P < .0001) for patients with an EGFR mutation," said Thomas E. Stinchcombe, MD, and Suresh S. Ramalingam, MD, in an editorial that accompanies the study results.
However, this unprecedented result for progression-free survival did not translate into a statistically significant improvement in overall survival, probably because most of the patients on placebo with an EGFR mutation received treatment with erlotinib upon progression, note Dr. Stinchcombe, from the University of North Carolina at Chapel Hill, and Dr. Ramalingam, from Emory University in Atlanta, Georgia.
This crossover effect on overall survival does not diminish the impressiveness of the improvement in progression-free survival in patients with an EGFR mutation — even if it is a small, limited group, suggest the editorialists.
"It has become clear that robust responses and prolonged [progression-free survival] outcomes with EGFR tyrosine-kinase inhibitors (TKIs) are limited to patients with an EGFR mutation," they summarize.
EGFR TKIs, which include gefitinib (Iressa, AstraZeneca), are well suited for maintenance therapy in this setting, the editorialists point out.
"Their proven efficacy, ease of administration, and favorable tolerability profile make them ideal for maintenance therapy," they write, adding that the quality-of-life indices in SATURN did not show any "significant differences" between the treatment and placebo groups.
In SATURN, the most common grade 3 or higher adverse events were rash (9% in the erlotinib group vs0% in the placebo group) and diarrhea (2% vs0%), report the study authors, led by Federico Cappuzzo, MD, from Ospedale Civile di Livorno in Italy.
Pemetrexed or Erlotinib for Patients With Wild-Type EGFR?
Maintenance therapy for NSCLC is defined as the use of an effective agent in the absence of disease progression following platinum-based combination chemotherapy, the editorialists explain.
An outstanding question for clinicians is whether or not erlotinib is the best choice for maintenance therapy in patients with wild-type EGFR.
Patients with wild-type EGFR accounted for 45% and 42% of the treatment and placebo groups, respectively, in the 889-patient SATURN trial.
But the trial results indicate that erlotinib was not highly effective in NSCLC patients with wild-type EGFR.
"The benefit of maintenance erlotinib compared with placebo in terms of progression-free survival and overall survival was modest for such patients," write Drs. Stinchcombe and Ramalingam, referring to the wild-type patients.
Pemetrexed is a better choice for maintenance therapy in patients with wild-type EGFR, suggest the editorialists.
Pemetrexed is "likely to be the preferred agent in patients with nonsquamous histology, based on the improvement in median survival of 5 months seen with pemetrexed compared with placebo," they opine, suggesting that patients with squamous cell carcinomas are unlikely to have the mutation.
Both pemetrexed and erlotinib are approved by the US Food and Drug Administration as maintenance therapies for patients with advanced NSCLC.
The editorialists remind clinicians that they should remain mindful that maintenance therapy is not for all patients with advanced NSCLC who have stable disease after chemotherapy.
"The decision to administer maintenance therapy should take into consideration the disease burden, extent of symptoms, the toxicities associated with first-line therapy, and patient preferences. While maintenance therapy might be appropriate for some patients, it might be less preferable for others," write Dr. Stinchcombe and Dr. Ramalingam.
The SATURN trial was funded by F. Hoffman-La Roche. Dr. Stinchcombe reports being on the speakers' bureau of Lilly and Genentech. Dr. Ramalingam reports working as a consultant for Genentech, Imclone, Syndax, Astellas, Amgen, and GlaxoSmithKline. Dr. Cappuzzo reports receiving honoraria from Roche, Eli-Lilly, AstraZeneca, and Boehringer; and receiving payment for development of educational presentations, including service on speakers' bureaus, from Roche, Eli-Lilly, AstraZeneca, and Boehringer.
Lancet Oncol. Published online May 20, 2010.

Clinical Context

The mainstay of treatment of advanced NSCLC is platinum-doublet chemotherapy, which is associated with a median overall survival duration of 8 to 11 months. Although most patients with advanced NSCLC will achieve some clinical response with first-line chemotherapy, the majority of these patients will also experience progressive disease within 2 to 3 months of the discontinuation of chemotherapy.

Unfortunately, prolonged treatment with platinum-based chemotherapy may result in higher toxicity with little survival benefit. Erlotinib, an oral EGFR TKI, may help to prolong survival duration after chemotherapy for advanced NSCLC, with less toxicity. The current study tests this hypothesis.

Study Highlights

• The study was completed at 110 sites in 26 countries. All study participants were at least 18 years old and had unresectable or metastatic NSCLC. Patients who previously received anti-EGFR agents or who had uncontrolled brain metastases were excluded from study participation.
• All participants completed 4 cycles of standard platinum-doublet chemotherapy.
• Study subjects without disease progression during chemotherapy were randomly assigned to receive erlotinib 150 mg/day or placebo. Study treatment was continued until disease progression, unacceptable toxicity, or death.
• The main study outcome was progression-free survival. Secondary outcomes included overall survival and quality of life.
• 1949 patients underwent screening and received first-line chemotherapy. The most common chemotherapy regimens were carboplatin plus gemcitabine, cisplatin plus gemcitabine, and carboplatin plus paclitaxel.
• 889 patients had stable disease or improvement during first-line chemotherapy, and these patients received erlotinib or placebo. The mean age of these participants was 60 years, and three quarters of subjects had stage IV cancer. The pathologic features of cancers were nearly equally divided between adenocarcinoma/bronchoalveolar carcinoma and squamous cell carcinoma.
• The median follow-up time was 11.4 months in the erlotinib group and 11.5 months in the placebo group.
• Median progression-free survival times were 12.3 and 11.1 weeks in the erlotinib and placebo groups, respectively, a significant difference (HR, 0.71).
• On examination of patients with EGFR-positive tumors only, erlotinib remained superior to placebo in progression-free survival (median, 12.3 vs 11.1 weeks; HR, 0.69).
• The median overall survival times in the erlotinib group and the placebo group were 12.0 and 11.0 months, respectively (HR, 0.81).
• Measurements of quality of life were similar in comparing the erlotinib group vs the placebo group.
• The rate of adverse events associated with erlotinib was similar to that in previous trials. Serious adverse events occurred in 11% of the patients receiving erlotinib and in 8% of patients receiving placebo. The most frequently reported serious adverse event was pneumonia. The most common adverse events overall with erlotinib were rash and diarrhea, which were usually not severe.
• 16% of participants receiving erlotinib required a dose reduction or interruption of treatment because of adverse events vs 3% of participants receiving placebo.

Clinical Implications

• The mainstay of treatment of advanced NSCLC is platinum-doublet chemotherapy, which is associated with a median overall survival duration of 8 to 11 months. The majority of patients with advanced NSCLC will achieve some clinical response with first-line chemotherapy, but progressive disease is common within 2 to 3 months of the discontinuation of chemotherapy.
• The current study demonstrates that maintenance therapy with erlotinib can improve progression-free and overall survival times among patients who respond to first-line chemotherapy of NSCLC. Quality-of-life scores were similar in comparing participants receiving erlotinib vs placebo.

Issues in the Treatment of Relapsed or Refractory Hodgkin Lymphoma: An Expert Interview With Dr. Craig Moskowitz

 

Hodgkin lymphoma (HL) is a relatively uncommon malignancy involving nodal and extranodal sites that can be very effectively treated. With 5- and 10-year survival rates of 85% and 81%, respectively,^[1] the disease has shown unprecedented improvements in survival rates in the past 3 decades.^[2] Indeed, cure rates for HL have increased so dramatically that treatment is often driven by considerations of long-term toxicity and secondary malignancy, particularly for patients with early- or intermediate-stage disease. Standard of care includes chemotherapy -- most often ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), but also potentially Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) -- with or without radiation therapy.^[3]
The outlook varies for patients with refractory or relapsed disease. High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT) is the standard of care, and cure can still be achieved. However, there is a subset of patients who are chemo-refractory to standard-dose salvage regimens and who fail or are not eligible for HSCT -- and who therefore require novel approaches to treatment. New agents, such as bendamustine, histone deacetylase (HDAC) inhibitors, and SGN-35, and novel strategies, such as reduced-intensity allogeneic therapy, are under study, with research ongoing into their effectiveness as well as how best they may be incorporated into standard treatment regimens. Preliminary results on some of these new agents were presented at the 2009 annual meeting of the American Society of Hematology (ASH).
On behalf of Medscape, Dina Acciai Basile, RPh, MBA, spoke with Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology-Memorial Sloan Kettering Cancer Center, Associate Member Lymphoma Transplant Services at Memorial Sloan-Kettering Cancer Center, and Associate Professor of Medicine at Weill Medical College of Cornell University, to discuss the latest advances in relapsed and refractory HL.
Medscape: Let's start briefly with first-line treatment of HL. What issues do you think need to be addressed?
Craig H. Moskowitz, MD: The main issues that I would identify in first-line treatment are late-treatment effects and the decreased use of radiation therapy (RT). To the first point: once patients have survived about 10 years past initial therapy, their cause of death is almost never from HL. It is from issues related to therapy.^[3] A critical aspect of treatment therefore is patient stratification: Do not overtreat the patients who are expected to do well, and do not undertreat the patients who are expected to do less well with primary therapy. But how do you distinguish?
There are 2 main ways to stratify patients: one used by the German Hodgkin Study Group (GSHG) and the other in US trials.^[3] The GSHG approach divides patients into 3 prognostic groups: early-stage favorable, early-stage unfavorable, and advanced-stage HL. The US approach divides patients into 4 risk groups: early-stage favorable, early-stage unfavorable, bulky-stage II, and advanced-stage disease. In addition, there is a different treatment strategy based on gender. Women with nonbulky disease are almost never administered RT, while men usually do receive RT as part of consolidation after primary chemotherapy. Although the assumptions underlying each of them differ -- the GHSG assumes there is only 1 chance, or at the most 2 chances, to be cured, while the US approach assumes 3 points of intervention for cure -- both approaches are an attempt to individualize treatment to have the best chance of cure without raising the subsequent risk for treatment-related toxicities. As such, the US treatment approach for favorable disease is most often ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine] alone, with RT use based on more risk factors. Patients who experience relapse are autotransplanted. If treatment fails, depending upon remission duration, the disease is still potentially curable with either a nonmyeloablative transplant from a matched related donor or an unrelated donor, or a cord blood transplant.
The second point, the decreased use of RT, relates to the risk for late-treatment effects as well as an increased use of fluorodeoxyglucose- positron emission tomography (FDG-PET) scanning, especially among patients with B symptoms, with bulky stage, or with poor risk, early-stage HL. PET scanning upstages patients to stage III or IV by finding disease in small lymph nodes below the diaphragm or in extranodal sites that we did not see before^[4] -- and these patients receive chemotherapy alone. In terms of late-treatment effects, the risk of developing secondary malignancies is highest in patients who receive RT as first-line therapy.^[3] This is particularly the case for women and breast cancer, and therefore the irradiation of women has been discouraged. Nevertheless, we are seeing more women with relapsed and refractory disease, so I should note that although we try to avoid RT in women because of fertility and breast cancer issues, not all women should be non-irradiated.
The 2 key points to remember in the first-line setting are: (1) the relapse rate is higher for patients who failed chemotherapy alone compared with those who failed combined modality therapy, and (2) patients who fail chemotherapy alone are still curable but need to undergo transplantation.
Medscape: When a patient presents with relapsed or refractory disease, what drives your treatment strategy?
Dr. Moskowitz: The approach I take to patients with relapsed and refractory HL is that they are curable. Indeed, at least half of patients with chemosensitive disease who undergo autotransplantation will be cured.^[5] However, as in all aggressive lymphomas, outcomes are very poor if the disease is not chemosensitive.
Although we have made progress reducing the toxicity and cost of HSCT, relapse and progression rates after HSCT have changed little in 10-15 years. CBV (cyclophosphamide, carmustine, etoposide) and BEAM (carmustine, etoposide, cytarabine, melphalan) are standard conditioning regimens, and there is no evidence to date that supports adding additional agents to these regimens to improve outcomes. Treatments continue to avoid RT, despite evidence that relapse occurs at the sites of bulky disease that should have been irradiated.^[6]
Still, there are a number of questions in the treatment of relapsed/refractory disease that arise: Can we develop reliable prognostic models that will predict outcomes for patients in a relapsed or refractory state? How can we incorporate FDG-PET scans into the way we treat patients? And how do we incorporate new agents and strategies into curative therapy for HL? Are there times when we should do an allogeneic transplant in lieu of an autotransplant -- keeping in mind that the disease must be in remission so that the graft vs lymphoma response that occurs in about 3-5 months can take effect?
In the 1990s, our group^[7] explored a new approach toward treatment by first giving 2 cycles of the ICE (ifosfamide, carboplatin, etoposide) chemotherapy regimen to determine chemosensitive disease and then performing a radiation-based transplant. This approach resulted in a 58% event-free survival at 43 months. In the study, we also identified 3 risk factors that predicted outcome: extranodal disease, B symptoms (fever, night sweats, and weight loss), and remission duration of 1 year or less. The more risk factors a patient had, the poorer the outcome -- such that patients with 0 or 1 risk factor had an 83% event-free survival vs 27% for those with 2 risk factors vs 10% for those with 3 risk factors.
More recently, we published a study in the British Journal of Hematology that evaluated patients treated according to risk factors while also examining the predictive value of FDG-PET scans.^[8] Patients with favorable risk factors received standard-dose salvage chemotherapy with 2 cycles of ICE and underwent autotransplantation after high-dose chemoradiotherapy if they responded. Intermediate-risk patients received augmented ICE and underwent autotransplantation if they responded. Patients with 3 risk factors received a tandem transplant -- either 2 autologous transplants or autologous followed by a mini allogeneic transplant. Survival tripled in patients with negative FDG-PET scans pre-transplant, with three fourths of patients who were FDG-PET negative being cured vs only one third of patients who were FDG-PET positive but with improvement on computed tomography (CT) scans, prior to transplant. The importance of the negative FDG-PET scan was also validated by another study.^[9] In 100 patients with 2 or fewer risk factors, we gave risk-adapted salvage chemotherapy and repeated their FDG-PET scan. If they were FDG-PET negative, patients underwent RT and autotransplantation. If they remained FDG-PET positive despite improvement on CT, patients did not receive transplantation but received additional chemotherapy for 2 months with gemcitabine, vinorelbine, and liposomal doxorubicin to try to achieve an FDG-PET-negative state. Those who improved when restaged underwent transplantation.
A key point is that it takes different levels of treatment to normalize the FDG-PET scan based on the number of patient risk factors. The goal of salvage chemotherapy in patients with relapsed and refractory HL should be to normalize the FDG-PET scan pre-transplant.
Medscape: Where do you see new agents or allogeneic transplant fitting in to that paradigm?
Dr. Moskowitz: There are 3 new classes of compounds that have activity in HL: bendamustine, antibody/drug conjugates, and HDAC inhibitors. When thinking broadly about new agents, I am less interested in using single-agent therapy. However, I am very interested in looking at maintenance therapy post-HSCT. Also, new agents such as HDAC inhibitors or antibodies can be incorporated into salvage chemotherapy to increase the number of patients in remission eligible for transplant. There are also phase 1 and 2 studies beginning to look at AVBD and the antibody SGN-35 in primary chemotherapy.
For patients who fail HSCT for HL, median survival is 2 years.^[10] Most patients are relatively young and in general good health, making them excellent candidates for investigational therapy. Our data suggest that if we can get patients into remission again and perform a second transplant, usually allogeneic, survival doubles. Although this approach is far from standard, my goal for patients who have failed autotransplant is to give investigational agents to potentially achieve an FDG-PET-negative state and prepare them for a nonablative allogeneic transplant. It was in this context that we studied bendamustine.
In my opinion, we also should consider allogeneic transplantation in lieu of autotransplantation for patients expected to have less than a 25% chance of being cured with an autotransplant following relapse from upfront therapy. Just reserving allogeneic transplantation for those who have failed autotransplantation is short-sighted. We have identified 2 subpopulations where allogeneic transplantation can be considered: patients with all 3 risk factors and patients who are still FDG-PET avid after salvage chemotherapy.
Medscape: Let's discuss each class of new agent. Shall we start with the new data on bendamustine presented at ASH in December?
Dr. Moskowitz: Bendamustine is an alkylating agent approved for chronic lymphocytic leukemia and indolent B cell rituximab-resistant non-Hodgkin lymphoma. It causes cell death via several pathways and is active against both quiescent and dividing cells. We presented data^[11] on the first 18 patients in an ongoing clinical trial who had failed autotransplant and, in some cases, allogeneic transplant. Of note, all responding patients had cytoreduction by the first planned restaging evaluation. Three fourths of patients responded -- meaning they could actually receive the allogeneic transplant. The key is to be ready to do the transplant when the patient is in a minimal disease state. The drug is well tolerated posttransplant -- no hair loss, minimal extramedullary toxicity, and very little nausea. There was some hematologic toxicity that was easily managed. In the future, we may also study bendamustine with other combinations.
Medscape: What about drug antibody conjugates?
Dr. Moskowitz: SGN-35 is an antiCD30 antibody conjugated to the antitubulin agent monomethyl auristatin E that causes cell cycle arrest and apoptosis by binding to CD30 and releasing the antimitotic into the cell. Remember that CD30 is a transmembrane glycoprotein receptor that is highly expressed on Reed-Sternberg cells with very limited expression on normal cells. The pivotal study is closed, and the data are not available yet. A recent poster at ASH^[12] discussed weekly dosing with SGN-35 in a heavily pretreated population of patients with relapsed and refractory HL. It was well tolerated and induced a 46% overall response rate, with 29% of patients attaining complete response. We are also enrolling a 400-patient international study in which relapsed, intermediate-risk patients follow their center's HSCT protocol and are randomly assigned SGN-35 or placebo for a year post-HSCT with the goal of doubling progression-free survival.
Medscape: Will you comment on HDAC inhibitors?
Dr. Moskowitz: HDAC inhibitors are small molecules that inhibit histone deacetylase. HDAC decreases oncogene expression, decreases angiogenesis, and induces cell cycle arrest and apoptosis. Vorinostat is approved for use in cutaneous T-cell lymphoma. Panabinostat is being studied in HL. Its single-agent activity is similar to that of SGN-35. There is an ongoing study looking at panabinostat maintenance post-HSCT.
Medscape: Do you have any final comments on the treatment of patients with relapsed/refractory HL?
Dr. Moskowitz: I believe we will see HL become a curable disease. The message for patients is one of hope. New agents will make continued improvements in outcomes possible.
Supported by an independent educational grant from Cephalon Oncology.

First-Line Treatment Options for Chronic Lymphocytic Leukemia: FCR and Beyond CME

Michael Hallek, MD

Introduction

During the past decade, the chemotherapy combination of fludarabine/cyclophosphamide (FC) emerged as standard therapy for the first-line treatment of chronic lymphocytic leukemia (CLL). More recently, the addition of rituximab (FCR) resulted in improved overall survival over FC, leading to approval by the US Food and Drug Administration (FDA) of FCR for use as both first- and second-line treatment. On the basis of these results, FCR is fast becoming the standard of care for healthy, fit patients with CLL. At the same time, however, a number of other agents, such as bendamustine, ofatumumab, GA101, alemtuzumab, Bcl-2 antagonists (ABT-263, oblimersen), lenalidomide, and flavopiridol, are emerging as treatment options for CLL. Whether these new agents will be reserved for cases in which FC or FCR is not appropriate or whether one or more may emerge as a viable alternative option to FC or FCR is still not clear, but research is under way. This article explores recent research into existing and emerging therapies for CLL.

Standard Therapy for CLL

Several randomized trials^[1-3] comparing FC with fludarabine monotherapy demonstrated improved complete response (CR) and overall response (OR) rates, as well as progression-free survival (PFS), with the use of FC, leading to the emergence of FC as the preferred chemotherapy combination for the treatment of previously untreated patients with CLL. With preclinical studies showing evidence for a synergy between rituximab and fludarabine,^[4] the monoclonal antibody rituximab was added to fludarabine-based regimens and investigated in several phase 2 trials.^[5-8] Results suggested improved ORs and CRs, as well as improved PFS and overall survival (OS), leading the German CLL Study Group to initiate a randomized, phase 3 trial comparing FCR with FC.
In the German CLL trial,^[9,10] 817 patients (median age, 61 years) with good physical fitness were randomly assigned to receive 6 courses of FC (n = 409) or FCR (n = 408). The study included 64% of patients at Binet stage B, 32% Binet C, and 5% Binet A. FCR induced a higher OR rate (92.8 vs 85.4%) and more CR (44.5 vs 22.9) (P < .001) than FC. In the initial analysis,^[9] PFS at 2 years was 76.6% in the FCR arm and 62.3% in the FC arm (P < .01). FCR treatment was more frequently associated with grade 3 and 4 neutropenia (FCR 34%; FC 21%), while other side effects were not increased. Treatment-related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. A systematic analysis of prognostic factors including molecular cytogenetics showed that the positive effect of FCR applied for most prognostic subgroups. However, FCR did not improve the PFS or OS of patients with a del(17p). These data were updated at the 2009 American Society of Hematology (ASH) annual meeting^[10] with a longer median observation time of 37.7 months. In the prolonged data, FCR continued to induce a higher OR rate (95.1% vs 88.4%) and more CRs (44.1% vs 21.8%; P < .001) than FC, as well as an improved PFS of 51.8 months vs 32.8 months for the FC group (P < .001). Most significantly, patients in the FCR arm had an improved OS compared with those in the FC arm. At 37.7 months, patients in the FCR arm had an OS of 84.1% vs 79% (P = .01) in the FC arm. In both arms, the median OS was not reached. For both PFS and OS, the largest benefit for FCR was observed in Binet stage A and B. As with the earlier reports, more patients in the FCR arm had hematologic adverse events, particularly neutropenia, but they did not have an increased infection rate. There were more deaths in the FC arm (86/396, 21.7%) than the FCR arm (65/404, 16.1%).
Taken together, the results show that FCR is superior to FC in the first-line treatment of physically fit patients with CLL. Therefore, the German CLL Study Group currently considers this combination to be standard of care for this group of patients.

Alternative Chemoimmunotherapy Combinations

Recently, an older chemotherapy option, bendamustine, and 2 new monoclonal antibodies, ofatumumab and alemtuzumab, were approved for treatment of CLL. Other novel therapies are also under consideration. In what appears to be a promising combination for first-line treatment, bendamustine has been combined with rituximab (BR), while results have been more mixed in some of the first-line chemoimmunotherapy combinations involving ofatumumab and alemtuzumab.
Bendamustine
The German CLL Study Group initially studied BR in patients with relapsed CLL.^[11] Results showed an OR rate of 77%, CR rate of 15%, and grade 3/4 neutropenia and thrombocytopenia rates of 12% and 9%, respectively -- response rates that were similar to those of the FCR regimen but with less neutropenia than the FCR regimen historically has had. On the strength of those results, the German CLL Study Group initiated a trial of BR in 117 patients (median age, 64 years) with previously untreated CLL.^[12] Results of the phase 2 trial were presented at ASH 2009. At a median follow-up of 15.4 months, patients had an OR of 91%, CR of 33%, and 85% were in remission. Major side effects were low, with grade 3/4 neutropenia and thrombocytopenia occurring in 6.5% and 6% of courses, respectively. On the basis of these promising results, the German CLL Study Group is currently conducting the CLL10 study, a randomized comparison of FCR and BR in patients with previously untreated CLL. At present, FCR remains the preferred option, but the results of this study are anxiously awaited.
Monoclonal Antibodies
Building on the success of the antiCD20 antigen rituximab, researchers have been investigating a number of other monoclonal antibodies. These include ofatumumab, a fully human CD20 antibody that binds to a different site on CD20 than rituximab; alemtuzumab, a recombinant, fully humanized, monoclonal antibody against the CD52 antigen; and lumiliximab, a primatized anti-CD23 antibody that recently failed in a randomized trial.
Alemtuzumab has been studied most closely as a therapeutic option for patients with poor prognostic features. Monotherapy has produced response rates starting at 33% in patients with advanced or refractory CLL,^[13-15] and it has proven efficacy in patients with high-risk genetic markers such as deletions of chromosome 11 or 17 (del(11q) and del(17p)), and p53 mutations.^[16,17] As such, it is under investigation in a number of combinations for first-line therapy. However, results of alemtuzumab combined with FC (FCA) have been disappointing so far, with FCA proving more toxic and less efficacious than FCR.^[18]
Presenters at ASH 2009^[19] reported on the combination of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) in high-risk patients with previously untreated CLL. Results in 60 patients were similar to those seen previously with FCR, with 92% OR, 70% CR rate, and comparable PFS and overall survival. Toxicities were increased, however, suggesting that this regimen does not add significantly to FCR but may be more toxic. Synergistic activity between fludarabine and alemtuzumab (FA) was investigated in a phase 2 trial enrolling patients with relapsed CLL.^[20] This combination proved feasible, safe, and effective. The German CLL Study Group is studying FCA in patients with relapsed/refractory CLL.^[21]
What role, if any, alemtuzumab has in first-line therapy will become more clear once the results from 2 phase 3 trials are presented. Unfortunately, one of the studies, a trial from the French study^[18] group comparing FCA with FCR in first-line therapy, was closed prematurely due to the higher toxicity observed in the FCA arm. In the other study, a first-line trial from the HOVON group, high-risk patients have been randomly assigned to receive either FC or FCA. Efficacy and toxicity results are awaited.
Ofatumumab has shown somewhat promising activity in patients with advanced CLL refractory to both fludarabine and alemtuzumab and in patients with fludarabine-refractory CLL inappropriate for alemtuzumab treatment.^[22] Response rates in these populations were 58% and 47%, respectively. Consequently, it has raised interest for its potential as first-line therapy in patients with high-risk CLL. A phase 2 study presented at ASH 2009 assessed ofatumumab in combination with FC (FCO) in a high-risk, previously untreated CLL population.^[23] OR was between 73% and 77%, with CR in 32% and 50% of patients (2 doses were assessed). These results were somewhat disappointing when compared with FCR, in particular with the high number of neutropenias observed for FCO in this trial. Ofatumumab does not seem to add much to current treatment options in CLL.
Lumiliximab showed a good safety profile with limited clinical activity in a phase 1 protocol.^[24] Preliminary results of a phase 1/2 study evaluating lumiliximab plus fludarabine, cyclophosphamide, and rituximab (L + FCR) in 31 patients with relapsed CD23+ CLL demonstrated an overall response rate of 71%, with 48% CR, 10% PR, and 13% unconfirmed PR,^[25] suggesting a possible improvement over the FCR regimen. However, an ongoing phase 3 study was closed early due to a lack of improvement over the FCR arm. It is unclear whether lumiliximab will have a role in CLL therapy.
Variations to FCR
The main drawback of FCR has been its myelotoxicity, particularly in elderly patients who have comorbidities. Therefore, variations on FCR have been investigated.
One such approach has been to use a dose-modified "FCR-Lite" regimen. This regimen -- which employs a reduced dose of the 2 cytostatic agents (fludarabine to 20 mg/m² and cyclophosphamide to 150 mg/m² days 2-4 during cycle 1 and days 1-3 in cycle 2-6) and an increased dose of rituximab (day 1 of cycle 1 at a dose of 375 mg/m²; cycles 2-6 on day 1 at 500 mg/m² preceding chemotherapy and on day 14 of each cycle) -- was investigated in a study of 50 untreated patients with CLL (median age, 58 years).^[26] Maintenance rituximab at 500 mg/m² was given every 3 months until progression. Responses were determined using the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines.^[27] In the study, the CR rate was 77%, with an OR rate of 100%. At a median follow-up of 2.4 years, all complete responders remained in CR, except for 1 patient who died of a myocardial infarction while still in remission. Five patients with PRs died within 2 years of completing FCR-Lite. Grade 3/4 neutropenia was documented in only 13% of cycles, a lower rate than that observed with the usual FCR regimen. With its lower toxicity but maintained efficacy, this regimen appears promising. However, it requires further testing in larger trials.
Another attempt at lowering the toxicity of FCR involved the substitution of pentostatin for fludarabine in FCR (a regimen known as PCR). A phase 3 randomized trial^[28] of FCR vs PCR in previously untreated and minimally treated CLL patients revealed no statistical differences between treatments in OS or response. However, there also were no significant differences in infection rate (fever > 101° F requiring antibiotics) -- the primary endpoint of this study -- between the 2 arms (31% in FCR and 34% in PCR).

Conclusions

At the present time, when choosing treatment, there are 3 potentially relevant points to consider:

• The physical condition (fitness and comorbidity) of the patient (independent of calendar age);
• The prognostic risk of the leukemia as determined by genetic and other prognostic factors; and
• The Rai or Binet stage of the disease.

Patients at early stage (Binet A and B, Rai 0-II) without symptoms usually do not require therapy. Treatment should be initiated in patients with advanced disease (Binet C, Rai III-IV) or active, symptomatic disease. Patients in good physical condition should be offered FCR, while those with comorbidities may be offered either chlorambucil or a dose-reduced fludarabine-containing regimen for symptom control. Finally, patients with symptomatic disease and with del(17p) or p53 mutations respond poorly to fludarabine or FC. Although they may respond to alemtuzumab mono- or combination therapy or to FCR, these responses usually have a short duration. Therefore, these patients are candidates for experimental treatment protocols and should be offered an allogeneic stem cell transplant whenever possible.
This activity is supported by an independent educational grant from Cephalon Oncology.

Skip the Clopidogrel Gene Test, Just Assay the Platelets, New Data Suggest

Shelley Wood

 

May 28, 2010 (Paris, France) — Worried about clopidogrel nonresponse? Skip the gene test and just check for platelet reactivity--that's the advice of Dr Laurent Bonello (Hôpital Université Nord, Marseilles, France), who presented new data to support this strategy here during a EuroPCR 2010 hotline session. In his study, one out of five patients who carried the now-infamous "poor-metabolizer" gene variant actually responded appropriately to an initial clopidogrel loading dose, while one out of two who were not carriers did not.

Dr Laurent Bonello

Bonello told heartwire that his study was in part a response to a recent FDA warning advising physicians that clopidogrel may have reduced benefits in people who are "poor metabolizers" and suggested that genetic testing could help identify patients who ineffectively convert clopidogrel to its active form. Studies show that people who carry loss-of-function variants of the liver enzyme CYP2C19 are at higher risk of stent thrombosis, MI, and death when receiving dual antiplatelet therapy with aspirin and clopidogrel. The FDA warning suggested that people identified as carriers of the 2C19* variants could be given other antiplatelet medications or alternative dosing strategies.
Bonello's study tested this second strategy. "We say, it's okay, you can still use clopidogrel, but you have to test," he explained to heartwire . "And it's not gene testing that you should be doing, it's platelet-reactivity testing."
Testing and Dosing
Bonello and colleagues performed gene and platelet-reactivity tests in a consecutive series of 411 non-ST-elevation acute coronary syndrome (NSTE-ACS) patients after they'd received a 600-mg loading dose of clopidogrel. A cutoff of 50% by vasodilator-stimulated phosphoprotein (VASP) index was used to define high (ie, >50%) on-treatment platelet reactivity. Patients who were found to have high on-treatment platelet reactivity and to be carriers of a mutant allele were given additional 600-mg doses of clopidogrel every 24 hours until a VASP <50% was achieved.
Gene tests showed 277 patients had no genetic variant of CYP2C19, while 134 (35.3%) carried at least one-loss-of-function CYP2C19 allele (11 homozygotes and 123 heterozygotes). After the initial loading dose, platelet reactivity was significantly higher among mutant carriers than among carriers of the wild-type gene (61.7 vs 49.2, p<0.001). After a second 600-mg loading dose, however, platelet reactivity was significantly reduced in carriers of the loss-of-function allele, dropping from a mean VASP index of 69.7% to 50.6% (p<0.0001).
Among the 123 heterozygotes, 88 had high on-treatment platelet reactivity, but after a second, third, or fourth loading dose, only 11 patients had a VASP index >50%. Among the homozygotes, just five out of 11 had high on-treatment platelet reactivity, which was normalized in all but one patient after a second, third, or fourth loading dose. For all 2C192* carriers, dose adjustment with up to three additional loading doses was effective in 88% of the carriers with high platelet reactivity after their initial clopidogrel dose. Importantly, no major TIMI bleeds were seen, and all four minor TIMI bleeds occurred in the wild-type carriers. The only other adverse event was a stent thrombosis, which occurred in a heterozygote who had failed successive dose adjustments.
"Increased and tailored loading dose of clopidogrel can overcome high on-treatment platelet reactivity in carriers of the loss-of-function 2C192* polymorphism," Bonello concluded. "Since studies have demonstrated the clinical benefit of dose adjustment in patients with high on-treatment platelet reactivity undergoing PCI, this therapeutic strategy may improve the prognosis of carriers of this loss-of-function polymorphism."
He also emphasized the shortcomings of gene testing alone. In his series, 20% of patients who were carriers of the polymorphism actually had a good response to the first loading dose of clopidogrel. And on the flip side, a full 50% of patients who were not carriers of the mutant genotype still had a platelet reactivity >50% after the initial loading dose.
"There are some determinants of platelet reactivity that are not genetic, so if you take only the genetic part, you will miss a lot of patients who have a high on-treatment platelet reactivity," he told heartwire .
Uncertainties Remain
Dr Laura Mauri (Brigham and Women's Hospital, Boston, MA), one of the session moderators, hinted that the FDA's warning has left operators uncertain as to just what it is they should be doing with their patients. "It's very difficult. The FDA has issued a statement about testing for genetics, and they've suggested that you may want to increase the long-term follow-up dose or change medications based on genetic testing. What is your recommendation?" she asked Bonello.
He responded saying he does not do any genetic testing in his practice. "I feel that platelet reactivity is more important than the genotype, because it includes more factors that are associated with low response to the drug. This is what we focus on, and we measure platelet reactivity routinely in all patients."

Dr Stephan Windecker

Mauri's comoderator, Dr Stephan Windecker (University Hospital, Bern, Switzerland), spoke with heartwire after the presentation, calling Bonello's study "very important, not only from the regulatory perspective, but from a practical perspective: whether you perform genetic testing vs just testing for platelet reactivity."
These findings "obviously would need to be tested in larger studies and with other measure of platelet reactivity," Windecker observed, noting that the VASP test is not the most widely used assay, although it is "certainly an established assay." It will also be very important to look at clinical outcomes after dose adjustment, he added.
"This is really a good hint that you don't need to perform genetic tests; you might be just as successful by just issuing repeated boluses. Yet I think the question remains--is this clinically relevant? Right now you have this effect on platelet reactivity, but does that translate clearly into a clinical effect? We don't know."
Bonello disclosed receiving grant support from Daiichi Sankyo-Eli Lilly.

Pfizer Halts Eplerenone HF Trial Early Due to Drug Benefit

Lisa Nainggolan

May 28, 2010 (New York, New York) — Pfizer is to halt recruitment of patients to the EMPHASIS-HF trial testing its selective aldosterone inhibitor eplerenone (Inspra) in mild heart-failure patients because of a significant benefit of the drug [1].
The trial, comparing eplerenone with placebo, when added to usual care for HF, had intended to enroll just over 3000 patients with NYHA stage 2 HF in 30 countries, with a planned end date of October 2011. Patients were randomized to receive either eplerenone 25 mg once daily or placebo, and at four weeks the dose of study drug could be increased to 50 mg per day if required. The trial was planned to continue until a total of 813 adjudicated primary end-point events were reported.
An interim analysis has shown that those treated with eplerenone have a significant reduction in risk of the primary end point, cardiovascular death or HF hospitalization, compared with those on placebo, according to a Pfizer statement.
The company says it is now working to ensure that all patients are informed of this decision, and an amendment to the protocol will be requested to allow all consenting patients to start treatment with eplerenone in an open-label extension of the study, after completing a close-out visit ending the double-blind, placebo-controlled phase.
Eplerenone, which has been called a "cleaner, safer" version of spironolactone, is approved for hypertension and for use in addition to optimal medical therapy early after acute MI in patients with congestive heart failure (CHF), on the basis of the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) study. But eplerenone is not yet approved for use in the patient population being studied in EMPHASIS-HF, those with mild HF.

AAP Retracts Controversial Policy on Female Genital Cutting

AAP Retracts Controversial Policy on Female Genital Cutting

Kathleen Louden


June 2, 2010 — The American Academy of Pediatrics (AAP) is again changing its policy on ritual female genital cutting (FGC) after advocacy groups protested the academy's recently revised policy statement regarding the excision of girls' external genitalia, which some African, Middle Eastern, and Asian cultures perform as a rite of passage.

The AAP board of directors voted on May 22 to retire the new policy, published in the May issue of the journal Pediatrics, and to immediately revise it because of the confusion it generated, AAP President Judith Palfrey, MD, told Medscape Pediatrics.

That policy statement expressed concern that girls from cultures that practice FGC who now live in the United States may be sent by their parents back to their native countries for a genital-altering procedure that can be harmful and even life-threatening. In the statement, which revised the academy's 1998 policy, the AAP's Committee on Bioethics wrote, "It might be more effective if federal and state laws enabled pediatricians to reach out to families by offering a ritual [clitoral] nick as a possible compromise to avoid greater harm."

Opposes "All Forms" of FGC

In an official statement that the AAP released to Medscape Pediatrics, the board writes: "The AAP does not endorse the practice of offering a 'clitoral nick.' This minimal pinprick is forbidden under federal law and the AAP does not recommend it to its members."

"The ethics committee will do a rewrite, which will reassert the AAP opposition to all forms of female genital cutting," stated Dr. Palfrey, a pediatrician at Children's Hospital Boston.

During a telephone interview with Medscape Pediatrics, Dr. Palfrey said the original comment about performing a medically unnecessary nick represented an academic discussion of options to stop this "awful" practice.

"This was never a recommendation," she stressed. "Obviously, having a discussion inside a policy statement is confusing. We regret this."

The new policy revision will appear in the July print issue of Pediatrics.

Committee members will explore noncutting options in working to eliminate all forms of FGC, Dr. Palfrey said.

Female genital mutilation, as many opponents of FGC call it, includes 4 types of cutting, according to the World Health Organization, which views it as a human rights violation. They are:

* removal of part or all of the clitoris;
* clitoridectomy with or without excision of the labia majora;
* infibulation, the most severe form, which involves excision of the clitoris and some or all of the labia minora, as well as suturing the remnant labia majora together to create a skin flap covering the urethra and vaginal opening except for a small hole; and
* picking, piercing, incising, scraping, and/or cauterizing the genital area for nonmedical purposes.

Controversy about the AAP policy arose after a May 6 New York Times article, in which a member of the academy's bioethics committee, Lainie Friedman Ross, MD, was quoted as saying a nick of the clitoris is "a last resort" but is as "benign" as ear piercing. "A just-say-no policy may end up alienating these families, who are going to then find an alternative that will do more harm than good," she told the New York Times.

Statement a Step Back

A debate about this less extensive form of FGC already took place in the late 1990s, said Nawal Nour, MD, an obstetrician/gynecologist at Brigham and Women's Hospital in Boston and director of the hospital's African Women's Health Center, which cares for African women who have undergone FGC in their home countries. That debate led to a US federal law against performing any nonmedical procedure on a female minor's genitals.

"Putting out a statement in 2010 trying to be culturally sensitive [by suggesting a procedure that is illegal in the United States] is going back 10 steps," Dr. Nour said about the now-retracted AAP policy.

She did not, however, object to the Academy's change in term from female genital mutilation in its 1998 policy to the more neutral female genital cutting in the revision, as some critics of FGC did. Many of the African women she treats use the term circumcision and do not see themselves as victims, Dr. Nour said. Cultures that practice female circumcision believe it promotes cleanliness, protects virginity, and provides group identity.

Born in the Sudan, Dr. Nour did not undergo FGC, although many girls she knew did, and is against it. Yet she says the media often portray parents who have their daughters circumcised as barbaric. "These are genuinely good, caring parents who are trying to preserve a culture," she said.

She said she talks in a nonjudgmental way to pregnant African mothers who are considering circumcising their daughters after birth. "I take every single argument why they think they should do it and try to educate them that this is not necessary, is illegal here, and has long-term health consequences," she said.

Problems include recurrent urinary tract and vaginal infections, infertility, painful sexual intercourse, and childbirth complications.

The WHO estimates that up to 140 million girls and women worldwide have undergone some form of FGC, usually between infancy and 15 years of age. In the United States, nearly 228,000 female immigrants or refugees have been cut or are at risk for being cut because they come from ethnic communities where FCG is prevalent, according to an analysis of 2000 US Census data. Conducted by the African Women's Health Center, the analysis found that this number grew by 35% from 1990.

A bill proposed last month in the US House of Representatives, the Girls Protection Act of 2010 (HR 5137), would also make it a crime to take a minor girl living in the United States outside the country for the purpose of FGC.
[CLOSE WINDOW]
Authors and Disclosures
Journalist
Kathleen Louden

Freelance writer, Gurnee, Illinois

Kathleen Louden is a freelance writer for Medscape.

Disclosure: Kathleen F. Louden has disclosed the following relevant financial relationships:
Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Loyola University Stritch School of Medicine, Department of Surgery
Received income in an amount equal to or greater than $250 from: Loyola Department of Surgery

Systemic Lupus Erythematosus and Pregnancy

Author: Ritu Khurana, MD, Assistant Professor of Medicine, Temple University Hospital
Coauthor(s): Robert E Wolf, MD, PhD, Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Introduction

Background

Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders that affect women during their childbearing years. Typical clinical symptoms of SLE include fatigue, fever, arthralgias, arthritis, a photosensitive rash, serositis, Raynaud phenomenon, glomerulonephritis, vasculitis, and hematologic abnormalities. Flares of SLE are uncommon during pregnancy and are often easily treated. The most common symptoms of these flares include arthritis, rashes, and fatigue.
SLE increases the risk of spontaneous abortion, intrauterine fetal death, preeclampsia, intrauterine growth retardation, and preterm birth. Prognoses for both mother and child are best when SLE is quiescent for at least 6 months before the pregnancy and when the mother's underlying renal function is stable and normal or near normal.
The mother's health and fetal development should be monitored frequently during pregnancy. In addition, an obstetrician with experience in high-risk care should conduct the follow-up of pregnant women with SLE.

Pathophysiology

The pathophysiology of disease activity during pregnancy remains unknown.
Increased SLE disease activity is expected during pregnancy because of increased levels of estrogen, prolactin, and T–helper cell 2 cytokines. The incidence of exacerbations during pregnancy and the postpartum period, especially in women in remission at the beginning of pregnancy, has been progressively diminishing in the last 30 years. Possible causes for flare-ups during the postpartum period include decreased levels of anti-inflammatory steroid, elevated levels of prolactin (ie, proinflammatory hormone), and changes in the neuroendocrine axis.

Frequency

United States

The prevalence of SLE is 14.6-50.8 cases per 100,000 general population.

The frequency of exacerbation or persistently active disease varies with disease activity at conception. Rates range from 7-33% in women who have been in remission for at least 6 months to 61-67% in women who have active disease at the time of conception.

In the United States, the overall average incidence of SLE between 1950 and 1990 was estimated to be 1.8-7.6 cases per 100,000 person-years.

International

Incidences in 4 European cohorts from Iceland, England, and Sweden were similar to those observed in the United States. Rates in these cohorts were 3.3-4.8 cases per 100,000 person-years.

Mortality/Morbidity

Over the past 50 years, the survival rate in patients with SLE has improved dramatically. In 1955, the 5-year survival rate was only 50%, whereas, in the 1990s, the 10-year survival rate approached or exceeded 90%, and the 20-year survival rate approached 70%. Factors contributing to this improvement include early diagnosis, increased potency of pharmaceutical agents, and improved treatments (eg, dialysis, kidney transplantation).
Nonetheless, despite improved survival rates, mortality rates among patients with SLE remain 3-5 times greater than those in the general population.

As with studies of incidence and prevalence, research about factors predictive of mortality in patients with SLE has focused on the patient's sex, race or ethnicity, socioeconomic status, or age at disease onset.

In one prospective study, hypertension during pregnancy, preterm delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism were more common in women with SLE than in women without SLE. In addition, fetal growth restriction and neonatal deaths were most often seen in association with SLE.

Race

• Evidence suggests that SLE is more common in African American groups than in white populations. In general, prognoses are worse in African American or Hispanic patients with SLE than in white patients.
• In North America and Europe, prognoses are worse in patients with SLE who are of Asian, Indian, African Caribbean, or Hispanic race than in white patients.
• When the prevalence of SLE is stratified by race, the prevalence among African Caribbean individuals was approximately 5 times the rate observed in people of white descent.
• In the United States, the prevalence of SLE in female African Americans ranges from 17.9-283 cases per 100,000.
• A West Indian study of female patients with SLE reported a prevalence of 83.8 cases per 100,000.

Sex

The incidence of lupus is dramatically higher in women than in men. The race- and sex-specific incidence rates of definite SLE per 100,000 persons were 0.4 (95% CI, 0.2-0.7) in white males, 3.5 (95% CI, 2.9-4.2) in white females, 0.7 (95% CI, 0-2) in African American males, and 9.2 (95% CI, 6.8-12.5) in African American females.

Age

SLE in pregnancy affects female adolescents and women of reproductive age.

• The incidence peaks between ages 15 and 45 years, ie, the childbearing years, when the female-to-male ratio is about 12:1.
• In patients with SLE that begins during childhood or later, the female-to-male ratio is approximately 2:1.

Clinical

History

History taking is targeted at identifying disease activity, complications related to pregnancy, and adverse effects of various medications.

• General considerations
  
  • Currently, more than 50% of all pregnancies in women with lupus have a normal outcome.
  • About 25% of women with lupus deliver healthy babies prematurely.
  • Fetal loss due to spontaneous abortion occurs in less than 20% of cases.
• Symptoms due to pregnancy
  
  • Nausea, vomiting, and morning sickness can occur during the first trimester.
  • The aforementioned symptoms may prevent absorption of medications.
• Symptoms suggestive of lupus disease activity
  
  • Constitutional symptoms may be present.
  • Most patients with lupus report fatigue during pregnancy.
  • The likelihood of developing renal disease during pregnancy is not increased if the patient was in remission at the time of conception.
• Differentiation of signs and symptoms of normal pregnancy from those of exacerbations of lupus
  
  • Differentiate malar rash from chloasma.
  • Differentiate proteinuria secondary to preeclampsia from proteinuria due to lupus nephritis.
  • Differentiate thrombocytopenia in pregnancy (ie, hemolysis, elevated liver enzyme levels, and low platelet counts [HELLP] syndrome) from thrombocytopenia of lupus exacerbation (ie, thrombocytopenic purpura [TTP] or idiopathic TTP [ITP]).
  • Pedal edema and fluid accumulation in joints, especially the knees, can occur in the late stages of pregnancy and should be differentiated from the arthritis of systemic lupus erythematosus (SLE).

Physical

• Flares
  
  • In general, pregnancy does not cause flares.
  • Flares that do develop often occur during the first or second trimester or during the first few months after delivery.
  • Most flares are mild and easily treated with small doses of corticosteroids.
• Renal disease
  
  • Patients with organ damage at the time of pregnancy may have difficulty because pregnancy adds to the burden on malfunctioning organs. This phenomenon is particularly important in patients with renal disease.
  • Pregnancy in women with lupus nephritis is associated with an increased risk of fetal loss (up to 75%) and with worsening of the renal and extrarenal manifestations, as shown in most studies. Although the incidence is not high, severe renal exacerbations are possible. Thus, women with lupus nephritis should be encouraged to delay pregnancy until the disease can be rendered inactive for at least 6 months.
  • Although the risk of adverse effects on the fetus are minimized if conception and pregnancy occur in the absence of glucocorticoids or other immunosuppressive drugs, continuing glucocorticoids at the lowest effective dose and/or cautious use of azathioprine may be preferred in some patients.
• Other comorbidities
  
  • Patients with preexisting hypertension, proteinuria, and azotemia are at an increased risk.
  • Pregnancy outcomes in women with SLE who receive renal transplants are remarkably similar to those of other transplant recipients.¹
• Preeclampsia
  
  • Preeclampsia is a frequent complication of pregnancy in SLE, occurring in approximately 13% of patients.
  • Preeclampsia is often difficult to distinguish from lupus nephritis. Laboratory testing is occasionally useful in distinguishing preeclampsia from nephritis.
  • Preeclampsia is most likely in patients with antiphospholipid antibodies, diabetes mellitus, or a previous episode of preeclampsia.
  • Pre-existing thrombocytopenia may also be a risk factor.
• Thrombosis
  
  • Pregnancy, and especially the postpartum period, represents an additional thrombotic risk in patients with SLE who have antiphospholipid antibodies.
  • Patients who are already taking warfarin because of a past venous or arterial thrombotic event should be switched to therapeutic doses of heparin (either unfractionated or low molecular weight heparin) as soon as the pregnancy is recognized.
  • Patients who have had only fetal losses or other pregnancy morbidity due to antiphospholipid antibody syndrome are treated with prophylactic doses of heparin and low-dose aspirin (81 mg) during subsequent pregnancies.
  • Currently, no accepted prophylaxis is available for women with SLE who have antiphospholipid antibodies and no past morbidity, although many consider the use of low-dose aspirin (81 mg), with or without hydroxychloroquine.
• Other causes of morbidity
  
  • In addition to the obvious morbidity from SLE flares and their treatment, other morbidity is also increased in a pregnancy associated with SLE.
  • Rates of urinary tract infections, diabetes mellitus, hypertension, preterm premature rupture of membranes, and preeclampsia are all increased in SLE.
• Risk assessment: Risk assessment in terms of checking for antiphospholipid antibodies (for a risk of fetal loss) and for anti-Ro and anti-La antibodies (for a risk of neonatal lupus) should be performed before pregnancy.
• Neonatal lupus
  
  • Neonatal lupus manifests as congenital heart block or as lupus rash. It is rare in SLE pregnancies, occurring in 3.5% of cases in one series. Neonatal lupus is highly associated with maternal anti-Ro (usually also with anti-La) antibodies, although the rash may occur with anti-RNP antibodies.
  • Because not all pregnancies in the setting of anti-Ro/La antibodies are associated with congenital heart block, prophylactic treatment is not appropriate. Instead, fetal 4-chamber cardiac echocardiography performed at 16-28 weeks' gestation is recommended.
  • If heart block of any degree is found, dexamethasone 4 mg/day is given to the mother because it crosses the placenta.
  • Third-degree heart block is rarely reversible.
  • In rare cases, neonatal lupus manifests as hepatic or hematologic involvement.
  • Most babies with congenital heart block can be delivered at term; if severe hydrops is present, early cesarean delivery is necessary.
  • Pacing is occasionally required in the neonate. Rare children with congenital heart block develop a connective tissue disease in adolescence.
• Fetal loss
  
  • Rates of pregnancy loss are substantially increased in patients with SLE compared with control groups.
  • Fetal loss is possible in any trimester.
  • First-trimester losses are associated with antiphospholipid antibodies and with markers of lupus activity (eg, low complement concentrations and increased anti–double-stranded DNA [anti-dsDNA] antibodies) and renal disease.
  • Late losses are associated with antiphospholipid antibodies.
  • Hypercoagulable states other than antiphospholipid antibody syndrome are also associated with increased fetal loss.
  • Women with SLE with fetal losses who are negative for antiphospholipid antibodies (including lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein 1) should be screened for genetic causes of hypercoagulability, such as factor V Leiden, prothrombin mutation, and hyperhomocysteinemia.
• Breastfeeding
  
  • Breastfeeding is feasible for most women with SLE. However, some medications may enter breast milk. Therefore, immunosuppressive agents are contraindicated, and long-acting NSAIDs are inadvisable. Short-acting NSAIDs, antimalarials, low-dose prednisone (<15-20 mg/d), warfarin, and heparin seem to be safe.
  • Women with anti-Ro/SSA and anti-La/SSB antibodies may have detectable amounts of these antibodies in breast milk, but no evidence suggests that neonatal lupus results from breastfeeding.
• Fertility: SLE is not associated with infertility unless the woman has been treated with cyclophosphamide, which leads to premature ovarian failure.

Differential Diagnoses

Glomerulonephritis, Diffuse Proliferative
Preeclampsia (Toxemia of Pregnancy)
Systemic Lupus Erythematosus

Other Problems to Be Considered

Lupus disease activity should be distinguished from other complications seen during pregnancy.
Renal disease secondary to an exacerbation of lupus may be difficult to differentiate from preeclampsia.
Lupus nephritis is often associated with proteinuria and/or an active urine sediment (RBCs, WBCs, and cellular casts), whereas only proteinuria is seen in patients with preeclampsia.
Flares of systemic lupus erythematosus (SLE) are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies; in comparison, complement levels are usually (but not always) increased in patients with preeclampsia.
In pregnant patients with renal disease, renal biopsy should be performed to differentiate preeclampsia from active lupus nephritis when differentiation on clinical grounds is not possible.
Thrombocytopenia, elevated serum levels of liver enzymes and uric acid, and decreased urinary excretion of calcium are more prominent in patients with preeclampsia than in those with lupus nephritis. However, thrombocytopenia may also be associated with antiphospholipid antibodies, thrombotic TTP, and immune thrombocytopenia, each of which may complicate pregnancy in women with SLE.

Workup

Laboratory Studies

• At the first visit after or when pregnancy is confirmed, the following assessments are recommended:
  
  • Physical examination, including blood pressure evaluation
  • Renal function tests, including determination of the glomerular filtration rate, urinalysis, and tests of the urine protein–to–urine creatinine ratio
  • CBC count
  • Test for anti-Ro/SSA and anti-La/SSB antibodies
  • Lupus anticoagulant and anticardiolipin antibody studies
  • Anti-dsDNA test
  • Complement (CH50 or C3 and C4) tests
• During the first 2 trimesters, a monthly platelet count or CBC count is recommended.
• The following evaluations are recommended at the end of each trimester of pregnancy:
  
  • Determination of the glomerular filtration rate and measurement of the urine protein–to–urine creatinine ratio
  • Anticardiolipin antibody measurement
  • Complement (CH50 or C3 and C4) test
  • Anti-dsDNA antibody study

Imaging Studies

• Women who have antibodies to Ro/SSA and/or La/SSB are at increased risk of pregnancies complicated by fetal heart block and may benefit from serial fetal echocardiographic monitoring.
• The goal is to detect fetal heart block at an early stage, when therapeutic interventions may prevent its progression.

Other Tests

• Fetal monitoring: Women with systemic lupus erythematosus (SLE) are at increased risk for intrauterine growth restriction and preterm birth. Therefore, menstrual dating should be confirmed with ultrasonography at the first prenatal visit to accurately estimate the gestational age.

Treatment

Medical Care

• Preconception counseling is recommended.
• Counsel patients about the teratogenicity and adverse effects of the medications used to treat systemic lupus erythematosus (SLE) before therapy is initiated.
• Patients may need to be reminded about the importance of using contraception while they are taking methotrexate, leflunomide, cyclophosphamide, and mycophenolate.
• Educate patients that, because of prolonged half-lives, some medications may need to be discontinued several months before the planned conception. In addition, measures may need to be undertaken to enhance elimination of some medications as soon as pregnancy is detected.
• In the absence of any historical features of antiphospholipid syndrome (recurrent pregnancy loss, venous or arterial thromboembolism), patients with lupus anticoagulant and/or high levels of anticardiolipin antibodies should receive low-dose aspirin. Some suggest the use of low-dose heparin and aspirin for such patients, even in the absence of previous pregnancy complications.
• Women with lupus and the antiphospholipid antibody syndrome require more frequent monitoring than those with SLE alone.
• In 2007, the European League Against Rheumatism (EULAR) released new recommendations for the treatment of SLE.

Surgical Care

Patients with SLE may have increased rates of emergency or cesarean delivery secondary to flares of renal disease or preeclampsia.

Consultations

A rheumatologist, an obstetrician experienced with high-risk care, and a nephrologist (if renal disease present or if it develops later) should work as a team to care for a pregnant patient with lupus.

Diet

• A low-salt diet is recommended in pregnancy to prevent weight increase and hypertension.
• An exercise program may help prevent bone loss and depression.
• Calcium and vitamin D supplementation may be advised to prevent osteoporosis.

Activity

Strenuous activity is best avoided when patients have flare-ups.

Medication

None of the medications used in the treatment of systemic lupus erythematosus (SLE) is absolutely safe during pregnancy. Hence, whether to use medications should be decided after careful assessment of the risks and benefits in consultation with the patient. During the first trimester, most of the drugs listed should be avoided.

Nonsteroidal anti-inflammatory drugs
(NSAIDs)

These agents have analgesic, antipyretic, and anti-inflammatory activity. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist. These may include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Ibuprofen (Motrin, Advil)

DOC for patients with mild to moderate pain. NSAIDs are used for their analgesic, anti-inflammatory, and antipyretic activities. NSAIDs should be stopped at the beginning of menstrual cycle when conception is planned; NSAIDs interfered with blastocyst implantation in animal studies. Possible maternal effects include prolonged gestation and labor, increased peripartum blood loss, and increased anemia. Potential adverse effects to the fetus include premature closure of ductus arteriosus, leading to pulmonary hypertension, impaired renal function with oligohydramnios, and increased cutaneous and intracranial bleeding. Short-acting NSAIDs (eg, ibuprofen, indomethacin, diclofenac) are preferred over long-acting agents.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; start at low end of dosing range and titrate prn; not to exceed 3.2 g/d

Pediatric

20-70 mg/kg/d PO divided tid/qid; start at low end of dosing range and titrate prn; not to exceed 2.4 g/d

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor prothrombin time (PT) (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may increase when administered concurrently

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Indomethacin (Indocin)

Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

25-50 mg PO bid/tid; 75 mg SR PO bid; not to exceed 200 mg/d

Pediatric

1-2 mg/kg/d PO divided bid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may increase when administered concurrently

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; GI bleeding or renal insufficiency

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in pre-existing renal disease or compromised renal perfusion; reversible leukopenia may occur; discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia is present

Disease modifying agents

These agents modify immune responses to diverse stimuli.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils and locomotion of neutrophils. Impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate at 200 mg equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

200-400 mg/d PO in divided doses

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; psoriasis; retinal and visual-field changes attributable to 4-aminoquinolones

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; perform periodic (eg, 6 mo) ophthalmologic examinations; test periodically for muscle weakness

Immunosuppressive drugs

These agents may suppress mechanisms responsible for autoimmune reactions.

Azathioprine (Imuran)

Purine analog that antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. In SLE, decreases levels of circulating B and T lymphocytes, immunoglobulin synthesis, and cytokine production. May be needed for patients with history of severe nephritis after cyclophosphamide or mycophenolate treatment. Can also be used as steroid-sparing agent.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

1 mg/kg/d PO for 6-8 wk; increase 0.5 mg/kg q4wk until response or dosage 2.5 mg/kg/d

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity to azathioprine or any component of the formulation

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Increases risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur; check TPMT level before therapy and monitor liver, renal, and hematologic function; pancreatitis or neonatal immunosuppression in rare cases

Mycophenolate mofetil (CellCept, Myfortic)

Prodrug enzymatically broken down into active metabolite MPA. Mycophenolic acid inhibits purine synthesis and decreases lymphocyte production and adhesion.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

2-3 g/d PO in divided doses

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Combination with acyclovir or ganciclovir may increase levels of both because of competition for renal tubular excretion; aluminum and/or magnesium present in some antacids, and cholestyramine-containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels; salicylates and azathioprine may increase toxicity; may decrease area under the concentration-time curve (AUC) for levonorgestrel; may decrease immune response to live-virus vaccine; may increase free-fraction levels of theophylline when used in combination

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection (monitor blood count); patients with severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increased free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with those of other immunosuppressants (0.9%); constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis are common; interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus may occur (rare); do not chew, crush, or cut Myfortic tab

Cyclophosphamide (Cytoxan)

Should not be used in pregnancy. Long-term treatment for lupus cerebritis and/or nephritis should be followed by yearly urine cytology to screen for bladder cancer.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

500-750 mg/m² IV qmo

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; severely depressed bone marrow function

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; young male patients should be counseled about sperm banking; women should be made aware of infertility risk

Cyclosporine A (Neoral, Sandimmune)

Cyclic peptide of 11 amino acids and natural product of fungi. Acts on T-cell replication and activity. Specific modulator of T-cell function. Depresses cell-mediated immune responses by inhibiting function of T helper cells. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.

Binds to cyclophilin (intracellular protein), which, in turn, prevents formation of interleukin (IL)–2 and subsequent recruitment of activated T cells. Mechanism of action involves inhibition of cytotoxic T cells, decreasing production of IL-2.

Bioavailability about 30%, but interindividual variability is considerable. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires drug to be present during first 24 h of antigenic exposure.

Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease) for various organs.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

2.5-5 mg/kg/d PO in divided doses

Pediatric

Administer as in adults

• Dosing
• Interactions
• Contraindications
• Precautions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; mutual inhibition with methylprednisolone that increases plasma levels of both

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; uncontrolled hypertension or malignancies; risk of preterm delivery and/or low birth weight; do not administer concomitantly with PUVA or UVB irradiation in psoriasis (may increase risk of cancer)

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; reserve IV use for only patients who cannot take PO; not teratogenic in animals or humans, but isolated case of renal damage reported in fetal rat

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

These drugs are used to treat the fetus in mothers with positive anti-SSA antibodies.

Dexamethasone (Decadron)

Has many pharmacologic benefits but clinically significant adverse effects. Stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, inhibits prostaglandin and proinflammatory cytokines (eg, tumor necrosis factor [TNF]–alpha, IL-6, IL-2, and interferon [IFN]–gamma). Inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Suppresses lymphocyte proliferation by direct cytolysis and inhibits mitosis. Breaks down granulocyte aggregates and improves pulmonary microcirculation.

Adverse effects include hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most adverse effects of corticosteroids are dose or duration dependent.

Readily absorbed from GI tract and metabolized in liver. Inactive metabolites excreted through kidneys. Lacks salt-retaining property of hydrocortisone.

Can be switched from IV to PO regimen in 1:1 ratio. Given to pregnant mother if fetal heart block detected in patients with anti-SSA antibodies. Crosses placenta.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

4 mg IV divided q6-12h

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines for immunization

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; viral, fungal, or tubercular skin infections

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Increases risk of several complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Prednisone (Deltasone, Orasone, Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. If steroid treatment desired for mother, prednisone, cortisone, or hydrocortisone should be chosen, as low concentration of active steroid reaches fetus.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

5-60 mg/d PO qd; administer lowest effective dose

Pediatric

0.05-2 mg/kg/d PO divided tid/qid

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; may alter levels of warfarin

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, fungal or tubercular skin infections; GI disease

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; high doses may result in growth retardation and cleft palate in fetus; if used during pregnancy, newborn must be monitored for adrenal suppression and infection

Methylprednisolone (Medrol, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear (PMN) leukocytes and reversing increased capillary permeability. Metabolized by placenta; thus, lowered concentrations reach fetus. Therefore, this is the preferred corticosteroid treatment.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

5-20 mg/d PO qd; 1 g/d for 3 d IV in life-threatening disease (renal disease secondary to lupus nephritis or cerebritis); administer lowest effective dose

Pediatric

Not established

Further Inpatient Care

• Patients may require admission for management of the complications of labor and delivery.

Further Outpatient Care

• All patients should be screened for postpartum depression.
• Patients must be monitored closely after delivery because some are likely to have flare-ups during the postpartum period.

Inpatient & Outpatient Medications

• Patients can breastfeed if they are not taking azathioprine, methotrexate, cyclophosphamide, or mycophenolate.
• Hydroxychloroquine is also secreted in breast milk; therefore, this drug should be used with caution. Hydroxychloroquine may displace bilirubin, resulting in kernicterus.
• Prednisone can be used safely during breastfeeding because small amounts (5% of the glucocorticoid dose) are secreted in breast milk. At doses of prednisone higher than 20 mg once or twice daily, breast milk should be pumped and discarded 4 hours after the dose to minimize drug exposure to the infant.
• NSAIDs can be used with caution in newborns without jaundice because NSAIDs can displace bilirubin and predispose the fetus to kernicterus.

Transfer

• Transfer to intensive care unit may be required for emergency intervention or monitoring during flares.

Deterrence/Prevention

• Patients should avoid pregnancy when lupus is active, especially in the presence of renal disease.
• Patients should use contraception while they are taking immunosuppressive disease-modifying drugs.

Complications

• Complications due to flare of the disease during pregnancy or the adverse effects of drugs on the fetus are possible.

Prognosis

• The long-term effect of pregnancy in patients with systemic lupus erythematosus (SLE) is unknown.
• Data from retrospective studies suggest no clinically significant adverse or positive effect of pregnancy on the course of SLE.

Patient Education

• Patients should be aware of the potential teratogenic effects of the drugs they are taking.
• Preconception counseling must be stressed.
• Use of contraception must be stressed frequently while patients are taking teratogenic medications.
• When treatment is recommended during pregnancy, patients must be informed of the potential adverse effects of the drugs on the fetus.

Miscellaneous

Medicolegal Pitfalls

• Failure to inform patients of the teratogenic effects of certain immunosuppressive drugs
• Failure to inform patients about the potential adverse maternal and fetal effects of the drugs recommended during pregnancy
• Failure to diagnose pregnancy before teratogenic disease-modifying agents are started
• Failure to inform patients to not breastfeed while they are taking certain drugs (eg, azathioprine, mycophenolate, cyclophosphamide)