August 2006 E-Newsletter

Initial Combination Therapy with Prednisone or Infliximab Improved Outcomes in Early Rheumatoid Arthritis More Than DMARDs Alone

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ACP Journal Club. 2006 May-Jun;144:72. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt Study). Arthritis Rheum. 2005;52:3381-90. [PubMed ID: 16258899]

Question

In patients with early rheumatoid arthritis (RA), which treatment regimen is most effective for prevention of joint damage and functional decline?

Methods

Design: Randomized controlled trial.

Allocation: Concealed.*

Blinding: Blinded (outcome assessors).*

Follow-up period: 1 year.

Setting: 20 hospitals in western Netherlands.

Patients: 508 patients > 18 years of age (mean age 54 y, 68% women) with active RA for < 2 years and no previous treatment with a disease-modifying antirheumatic drug (DMARD).

Intervention: Group 1 (n = 126): sequential monotherapy with methotrexate (MTX) 15 mg/wk, followed stepwise, if Disease Activity Score in 44 joints (DAS44) > 2.4, by MTX 25 to 30 mg/wk, then monotherapy with sulfasalazine (SSZ) 2000 to 3000 mg/d, and then leflunomide 20 mg/d. Group 2 (n = 121): step-up combination therapy starting with MTX as above, then, if DAS44 still > 2.4, addition of SSZ, then hydroxychloroquine 400 mg/d, and then prednisone 7.5 mg/d. Group 3 (n = 133): combined therapy with prednisone 60 mg/d (tapered in 7 wk to 7.5 mg/d), MTX 7.5 mg/wk (increased to 25 to 30 mg/wk if DAS44 > 2.4), and SSZ 2000 mg/d. Group 4 (n = 128): combined therapy with infliximab 3 mg/kg at week 0, 2, and 6, then every 8 weeks (dose was increased stepwise if DAS44 > 2.4, up to 10 mg/kg) and MTX 25 to 30 mg/wk. Treatment adjustments were guided by DAS44, which was measured every 3 months. For responding patients, drugs were tapered to monotherapy at a maintenance dose; treatment could be reintroduced if disease activity flared.

Outcomes: Change in joint damage in the hands and feet assessed by radiography (erosion score [0 to 280], joint space narrowing score [0 to 168], and total of the 2 scores), functional disability (assessed by the Health Assessment Questionnaire [0 to 3]), clinical remission (DAS44 < 1.6), and adverse events.

Patient follow-up: 92% to 97% (intention-to-treat analysis).

Main results

Groups 3 and 4 showed more rapid response to treatment and improvement in function than groups 1 and 2. At 1 year, groups 3 and 4 had less increase in joint damage scores than groups 1 and 2 (Table). Functional disability was lower in groups 3 and 4 than in group 1 (Table). Clinical remission was achieved by 32% of patients; each group had similar remission rates and mean DAS44 scores. Groups did not differ for adverse events.

Conclusion

In patients with early rheumatoid arthritis, initial treatment with prednisone or infliximab in combination with disease-modifying antirheumatic drugs (DMARDs) resulted in less joint damage and better functional outcome than sequential monotherapy or step-up combination therapy with DMARDs alone.

Sources of funding: Dutch College of Health Insurances; Schering-Plough BV; Centocor Inc.

For correspondence: Dr. Y.P. Goekoop-Ruiterman, Leiden University Medical Center, Leiden, The Netherlands. E-mail y.p.m.goekoop@lumc.nl.

*See Glossary.

4 treatment regimens for early rheumatoid arthritis at 1 year†

Commentary

Aggressive treatment of early RA has been shown to limit functional disability and radiographic progression. However, amid the increasing array of therapeutic options, the most effective treatment algorithm has yet to be determined. Currently, many rheumatologists begin therapy of early RA with either sequential substitution monotherapy (as in group 1 of the BeSt trial by Goekoop-Ruiterman and colleagues) or with step-up, add-on therapy (as in group 2). The BeSt trial encourages us to push beyond these options. It corroborates such previous trials as TICORA (1) and COBRA (2), showing that early, aggressive combination therapy, including either prednisone or infliximab, results in earlier functional improvement and diminishes radiographic progression of erosions at 1 year.

Although the radiographic progression differences at 1 year were statistically significant, their clinical effect remains uncertain. More than 40% of participants in groups 1 and 2 sustained adequate suppression of disease with MTX monotherapy, suggesting that not all patients need aggressive combination therapy. Identification of patient subgroups with good or poor response to different therapeutic options is vital if we are to optimize our use of these expensive, potentially toxic interventions. The duration of follow-up in the BeSt trial was comparatively short, and the long-term morbidity associated with high-dose steroids and anti–tumor necrosis factor use still needs to be evaluated.

The study by Goekoop-Ruiterman and colleagues provides provocative evidence that early, effective suppression of disease activity can lessen joint damage and, by extension, potentially induce long-term remission for many patients with RA.

Michael York, MD
David J. Hunter, MD
Boston University School of Medicine
Boston, Massachusetts, USA

References

1. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263-9. [PubMed ID: 15262104]

2. Landewé RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum. 2002;46:347-56. [PubMed ID: 11840436]

Internal Medicine Interest Group of the Month: University of Missouri, Columbia School of Medicine

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These are exciting times for the Association of Student Internists at the University of Missouri- Columbia! The 2005-2006 school year was very beneficial for our students. Our organization provided quarterly meetings to nearly seventy members on popular student-centered topics such as “Life as a Resident,” and “Opportunities in Internal Medicine.” Departmental support helped sponsor these meetings, as well as to fund student travel to conferences. Thanks to their financial support, 10 students were able to represent our school at the national ACP conference in April 2006.

The 2006-2007 year will offer many new exciting prospects. We look forward to our members collaborating with faculty and residents in the areas of research and case reviews. In addition to our quarterly meetings and brown-bag lunches, members can participate in new community outreach opportunities. Students are eager to attend the Missouri ACP Chapter Scientific Meeting in September 2006. Plans are also being made to attend Internal Medicine 2007, the national ACP scientific conference, in San Diego this coming April. With such strong membership and departmental support, the University of Missouri-Columbia chapter anticipates a productive and exciting year.

Students of University of Missouri-Columbia School of Medicine at the 2006 ACP conference in Philadelphia. (From left to right) Sarah Smitherman; Craig Karpman; Marina Litvin; Brian Fuller; Kerry Massman; Ben Morrison; Phil Hart; Zach Hugo; Laura Hesemann; Jason Pettus.

Congratulations to 2005-2006 Winners of the 40% Medical School Awards Program!

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Fifteen schools were awarded Certificates of Merit for having high overall Medical Student Membership in the ACP. This award was given to all schools whose Medical Student Membership met or exceeded 40% of the total student body for the entire membership year, which began July 1, 2005 and ended June 30, 2006. Schools that attained this membership threshold include:

University of Hawaii (77.2%)
Virginia Commonwealth University (73.4%)
Louisiana State University, New Orleans (60%)
Creighton University (56.7%)
Florida State University (53.2%)
University of Utah (48.3%)
Mercer University (44.9%)
University of Mississippi (43.8%)
University of Vermont (42.4%)
University of California, Davis (42.1%)
University of North Texas (41.7%)
University of Medicine and Dentistry of NJ, Stratford (40.1%)
University of California, Irvine (40%)
Memorial University of Newfoundland (40%)
Oregon Health Sciences University (40%)

Congratulations to these schools for their high level of involvement with the ACP! For having the highest overall percentages of Medical Student Membership, University of Hawaii was awarded $300 and Virginia Commonwealth University was awarded $200 in support of internal medicine interest group activities. For information about the Medical School Awards Program, please contact Patty Moore, Medical Student Coordinator, by e-mail at pmoore@acponline.org.

MKSAP Question 1

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A 33-year-old man comes to a clinic for evaluation of a rash. He has severe seborrheic dermatitis. He has tried hydrocortisone cream on his face without much benefit.

What is the most appropriate next step in the management of this patient?

( A ) Coal tar shampoo
( B ) Doxycycline
( C ) Emollients
( D ) Risk factor assessment for human immune deficiency disease
( E ) Skin biopsy

MKSAP Question 2

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A 75-year-old female nursing home resident is brought to the emergency department because of a 2-day history of fever and generalized weakness. She requires a chronic indwelling urinary catheter.

On physical examination, temperature is 38.4 °C (101.1 °F), pulse rate is 95/min, respiration rate is 22/min, and blood pressure is 132/72 mm Hg. Examination findings are otherwise normal. The leukocyte count is 13,000/µL (with 11% immature band forms). Urinalysis shows 20 to 25 leukocytes/hpf. A complete metabolic profile is normal. Arterial oxygen saturation is 95% by pulse oximetry with the patient breathing room air. Urine culture and two sets of blood cultures obtained yesterday in the nursing home are growing Escherichia coli.

Which of the following terms best describes this patient's illness?

( A ) Bacteremia
( B ) Septic shock
( C ) Sepsis
( D ) Severe sepsis
( E ) Systemic inflammatory response syndrome

MKSAP Answer 1

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Answer: D

Educational Objective: Recognize the association between human immunodeficiency virus infection and severe seborrheic dermatitis.

This patient presents with extensive seborrheic dermatitis, which has been minimally responsive to low-potency corticosteroid therapy. It is important to recognize the possibility that severe, recalcitrant seborrheic dermatitis may be a manifestation of underlying human immunodeficiency virus (HIV) disease and to assess the patient for HIV risk factors. Seborrheic dermatitis is a common cutaneous finding in patients with HIV disease. In one study, 23.8% of HIV-infected patients were found to have seborrheic dermatitis at baseline. The severity of seborrheic dermatitis has been correlated with increasing progression of disease. Recognition of refractory seborrheic dermatitis or extensive disease should prompt clinical evaluation for the possibility of underlying HIV disease. A skin biopsy is not necessary. Coal tar is a treatment for psoriasis, not seborrheic dermatitis. Doxycycline is used in the treatment of acne and will not benefit this patient. Emollients are useful in the treatment of eczema, not seborrheic dermatitis.

References

Schaub NA, Drewe J, Sponagel L, Gilli L, Courvoisier S, Gyr N, et al. Is there a relation between risk groups or initial CD4 T cell counts and prevalence of seborrheic dermatitis in HIV-infected patients? Dermatology. 1999;198:126-9. PMID: 10325457[PubMed]

MKSAP Answer 2

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Answer: C

Educational Objective: Recognize the clinical manifestations of sepsis, and differentiate this condition from systemic inflammatory response syndrome, severe sepsis, bacteremia, and septic shock.

Although this patient has documented bacteremia (defined as the presence of bacteria in the blood confirmed by culture), she also has evidence of a systemic response to infection (fever, tachycardia, tachypnea, and an elevated leukocyte count, with immature band forms). She does not have organ dysfunction or perfusion abnormalities, which occur in patients with severe sepsis or septic shock. Therefore, the term that best defines her illness is sepsis. The American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome are as follows:

Systemic inflammatory response syndrome (SIRS): The systemic inflammatory response to a wide variety of severe clinical insults, manifested by at least two of the following conditions: temperature greater than 38 °C (100.4 °F) or less than 36 °C (96.8 °F), heart rate greater than 90/min, respiration rate greater than 20/min or arterial blood Pco2 less than 32 mm Hg, and leukocyte count greater than 12,000/µL or less than 4000/µL or with more than 10% immature band forms.

Sepsis: The systemic inflammatory response to a documented infection. In association with infection, the manifestations of sepsis are the same as those described for SIRS.

Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension.

Septic shock: A subset of severe sepsis, defined as sepsis-induced hypotension, despite adequate fluid resuscitation, plus the presence of perfusion abnormalities. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they develop hypoperfusion abnormalities or organ dysfunction; however, they would still be considered to have septic shock.

Multiple organ dysfunction syndrome: The presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

References

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-74. PMID: 1597042[PubMed]

Student Members Receive a 30% Discount When Ordering MKSAP for Students 3

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MKSAP for Students 3 includes over 400 patient-centered self-assessment questions and their answers in print and on CD-ROM. Designed for medical students participating in their clerkship rotation, the questions help define and assess a student’s mastery of the core knowledge base requisite to internal medicine education in medical school. The questions reflect the daily management dilemmas faced by internal medicine physicians and when coupled with the answer critiques, provide a focused, concise review of important content.

New in MKSAP for Students 3:

  • All new questions and critiques
  • More topics and chapters
  • 12 electrocardiogram questions
  • 24 color figure dermatology questions

To order MKSAP for Students 3 please visit here.

Enroll in ACP’s Key Contact Program

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