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Case Report/Case Series |

Dermatomyositis Induced by Anti–Tumor Necrosis Factor in a Patient With Juvenile Idiopathic Arthritis FREE

Stephanie W. Liu, MD1; Nicole F. Velez, MD1; Christina Lam, MD1; Alisa Femia, MD1; Scott R. Granter, MD2; Henry B. Townsend, MD3; Ruth Ann Vleugels, MD, MPH1
[+] Author Affiliations
1Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
2Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
3Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham
JAMA Dermatol. 2013;149(10):1204-1208. doi:10.1001/jamadermatol.2013.5220.
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Published online

Importance  Biologic therapies, including anti–tumor necrosis factor (TNF) agents, are increasingly used to treat a variety of autoimmune diseases. Paradoxically, these agents have been reported to induce some of the very diseases they were designed to treat, including dermatomyositis (DM). We describe the first case of anti-TNF–associated DM without muscle involvement presenting in an adult patient with a history of arthritis since childhood. This cutaneous eruption recurred after rechallenge with an alternate anti-TNF agent.

Observations  A 46-year-old man with juvenile idiopathic arthritis developed a pruritic cutaneous eruption while receiving etanercept. Given concern about a drug-induced eruption, etanercept therapy was discontinued and the cutaneous findings improved. However, after rechallenge with adalimumab, he developed similar findings consistent with the skin manifestations of DM. After discontinuation of all anti-TNF drug therapy and the addition of methotrexate sodium, his eruption improved.

Conclusions and Relevance  Because the use of these agents is increasing, practitioners should be aware of the possibility of anti-TNF–induced autoimmune disorders, including DM. The case described herein is unique in that anti-TNF–induced autoimmune disease occurred in a patient with existing arthritis since childhood and recurred with rechallenge, adding further evidence to support the existence of anti-TNF–induced DM.

Figures in this Article

Biologic therapies, including anti–tumor necrosis factor (TNF) agents, are increasingly used to treat a variety of autoimmune diseases. However, these agents can induce some of the very diseases they were designed to treat, including dermatomyositis (DM). Herein, we describe a patient with a history of juvenile idiopathic arthritis (JIA) who developed anti-TNF–associated DM without muscle involvement.

A 46-year-old man with JIA receiving long-term low-dose prednisone therapy (3-4 mg/d) was initiated on etanercept for joint disease by his rheumatologist. He had a history of severe JIA starting at 10 years of age, with evidence of erosive changes in the hands and wrists. The disease was only partially responsive to therapies that included methotrexate sodium and diclofenac. For the first 10 years of treatment with etanercept, the patient exhibited minimal adherence with therapy, using injections sporadically every 5 to 6 weeks. However, within 2 months of beginning regular weekly etanercept injections, he developed a pruritic eruption on the face, trunk, and upper extremities. He also noted erythematous, scaly papules on the dorsal hands, particularly over the knuckles, and erythema around the nail folds. These new features were exacerbated by sun exposure. Etanercept therapy was discontinued, and the patient’s prednisone dosage was increased to 20 mg/d for his skin and joint symptoms. His cutaneous eruption slowly resolved over the next several months. One year later, due to persistent joint pain, the patient was initiated on adalimumab therapy. After 2 doses of adalimumab, the cutaneous eruption recurred with similar erythema of the face, chest, and arms and intermittent swelling and erythema over the eyelids. The papules on the dorsal hands returned along with the nail fold changes. Photoexacerbation was again noted. The patient continued to have these skin lesions for 10 months with an unclear diagnosis, during which time he was maintained on prednisone at a dosage of 20 mg/d. He was then referred to the dermatology department.

The patient described intense pruritus affecting his face, trunk, and extremities. He denied muscle weakness, shortness of breath, and dysphagia. The physical examination revealed facial erythema and a heliotrope eruption (Figure 1). He had poikilodermatous patches and thin plaques on the neck, chest, back, flank, and thighs, as well as erosions in the areas of cutaneous involvement on the lateral thighs (Figure 2). The patient had Gottron papules and periungual erythema with cuticular hypertrophy and telangiectatic vessels (Figure 3). A clinical diagnosis of DM was suspected, and a punch biopsy was performed on the patient’s right posterior shoulder. Results of the biopsy specimen showed a vacuolar interface dermatitis. High-power resolution of the dermal-epidermal junction demonstrated scattered lymphocytes associated with loss of the basal cell layer, apoptotic cells, and reactive squamous changes (Figure 4). Throughout the dermis, bluish-gray mucin was seen between collagen bundles (Figure 4). These findings were suggestive of connective tissue disease.

Place holder to copy figure label and caption
Figure 1.
Facial Findings of Dermatomyositis

The patient was noted to have midfacial erythema and a heliotrope eruption of the upper eyelids.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Lateral Thigh Findings of Dermatomyositis

The patient was noted to have poikilodermatous patches and thin plaques with cutaneous erosions on the lateral thigh.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Dorsal Hand Findings of Dermatomyositis

The patient was noted to have Gottron papules (A) and periungual erythema with cuticular hypertrophy and telangiectatic vessels (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Punch Biopsy Specimen From the Inflammatory Eruption on the Patient’s Right Shoulder

Scattered lymphocytes associated with loss of the basal cell layer, apoptotic cells, and reactive squamous changes are seen at the dermal-epidermal junction (A), with bluish-gray mucin between collagen bundles throughout the dermis (B) (original magnification ×400).

Graphic Jump Location

Laboratory results included negative antinuclear and anti–Jo-1 autoantibodies. Levels of creatinine kinase, aspartate aminotransferase, alanine aminotransferase, and aldolase were within reference limits. Because the patient denied muscle symptoms and had no evidence of muscle disease on physical examination or laboratory studies, additional studies (including electromyography, magnetic resonance imaging, and muscle biopsy) were not performed. A malignancy workup, including a full physical examination, complete blood cell count, comprehensive metabolic panel, stool occult blood testing, and prostate-specific antigen levels, as well as computed tomographic scans of the chest, abdomen, and pelvis, yielded unremarkable findings. Results of pulmonary function tests with diffusion capacity were also normal. Based on the patient’s history, including onset of the eruption during etanercept therapy followed by recurrence while taking adalimumab, as well as clinical and biopsy findings, a diagnosis of DM associated with anti-TNF inhibitor therapy was made.

Anti-TNF therapy was discontinued and treatment with oral methotrexate sodium was initiated at a dosage of 10 mg/wk and titrated up to 20 mg/wk, in addition to continuation of prednisone therapy. Aggressive photoprotection was recommended, and topical corticosteroid therapy was initiated. He had previously been prescribed hydroxychloroquine sulfate for his JIA but developed headaches, prompting discontinuation. The patient noted gradual improvement of pruritus and erythema once anti-TNF therapy was discontinued. He continued methotrexate therapy for 6 months while his prednisone dosage was successfully tapered from 20 to 5 mg/d. Although the patient’s cutaneous DM improved, his JIA remained active with significant joint symptoms. He has been reluctant to pursue other novel therapies for arthritis due to concern about the possibility of future drug reactions. He continues to follow up with both the dermatology and rheumatology departments.

Biologic therapies, including anti-TNF agents, are increasingly used to treat a variety of autoimmune diseases. Paradoxically, these agents have been reported to induce some of the diseases they were designed to treat.1 Anti-TNF therapy has been associated with various autoimmune phenomena, including lupus-like syndrome, cutaneous lupus, vasculitis, psoriasis, demyelinating neurologic diseases, sarcoidosis, and interstitial lung disease.1,2 Psoriasiform eruptions, a lupus-like syndrome, and vasculitis are the most frequently reported autoimmune sequelae.24 However, anti-TNF–associated DM is rare, accounting for less than 1% of reported cases of anti-TNF–induced autoimmune phenomenon. In the largest case series of 4 patients, 3 of the patients did not have a diagnosis of DM before starting anti-TNF therapy. The remaining 1 patient had dramatic worsening of existing DM-associated pulmonary symptoms within 2 months of starting anti-TNF therapy.3

In the 12 cases of anti-TNF–induced DM, polymyositis (PM), or antisynthetase syndrome reported in the literature to date, 11 patients had an underlying diagnosis of rheumatoid arthritis512 (Table). The remaining case had an underlying diagnosis of Crohn disease. Seven cases of anti-TNF–induced DM,3,57 3 cases of anti-TNF–induced PM,810 and 2 cases of antisynthetase syndrome11,12 associated with a TNF inhibitor have been reported. In these reports, the time of onset between the initiation of anti-TNF therapy and DM, PM, or antisynthetase syndrome ranged from 2 to 54 months. In the 12 previously reported cases, 13 anti-TNF inhibitors were used, with 1 patient treated sequentially with etanercept followed by adalimumab. The most frequent anti-TNF therapy associated was etanercept (6 of 13), followed by adalimumab (5 of 13) and infliximab (2 of 13).

Table Graphic Jump LocationTable.  Clinical Characteristics of Reported Patients Who Developed DM, PM, or AS After Anti-TNF Therapy

To our knowledge, this case of anti-TNF–associated DM is the first to present in an adult patient with a history of an autoimmune arthritis since childhood. This history is important because patients with DM or PM can develop arthritis. In addition, patients can present with overlapping connective tissue diseases. For these reasons, in earlier case reports of anti-TNF–associated DM, causality has been difficult to prove. Questions have persisted as to whether the arthritis that preceded the development of DM was merely an earlier feature of the DM itself, calling into question the theory that the DM findings that developed during anti-TNF therapy were, in fact, drug induced.

Therefore, it has frequently been questioned whether the patients described in these case reports truly had an inflammatory arthropathy before starting anti-TNF therapy or whether the arthritis was an early symptom of evolving DM. In such patients, DM might be initially misdiagnosed as an inflammatory arthritis. Furthermore, it has been suggested that there is an overlap between DM and rheumatoid arthritis in 2.6% to 20% of cases.13 In a recent retrospective review, among 75 patients with PM or DM, 5 (6.7%) developed PM or DM from 0.25 to 23 years after a diagnosis of rheumatoid arthritis.14

The causality of the cutaneous features of DM from anti-TNF therapy is clear in the case presented herein, given the long-standing history of arthritis from childhood, the recurrence of symptoms after rechallenge with a second anti-TNF agent, and improvement after discontinuation of anti-TNF therapy. In addition, only 1 other case in the literature has reported recurrence of anti-TNF–induced DM symptoms after rechallenge with a second anti-TNF agent, in that case with adalimumab followed by infliximab.5

With regard to anti-TNF–associated autoimmune diseases, the question remains whether rechallenge with another anti-TNF inhibitor is safe. In one of the largest registries of patients with autoimmune diseases triggered by licensed biologic agents, 54 cases in which anti-TNF therapy was reinitiated to treat the underlying disease once the anti-TNF–induced autoimmune disease resolved have been reported. In 17 cases, the same anti-TNF therapy was selected. Recurrence of the induced autoimmune disease was noted in 11 of 17 cases (65%). In the remaining 37 cases, an alternative anti-TNF agent was used. Recurrence or exacerbation was observed in only 10 of 37 cases (27%).1 Notably, our patient’s cutaneous manifestations of DM recurred with a second anti-TNF agent.

The case presented herein is also unique because the patient has had no evidence of muscle disease to date. Given that this patient was receiving low-dose prednisone, making it impossible to rule out partially treated muscle involvement, and the fact that his cutaneous findings were likely drug induced, we cannot formally categorize his disease as clinically amyopathic DM as per the Sontheimer criteria15 for this disease subset. However, the patient had the cutaneous findings of DM for more than 6 months before initiation of immunosuppressive therapy with medications used specifically for this eruption. None of the 7 previously reported cases of anti-TNF–associated DM have lacked muscle involvement. Our patient has denied symptoms of muscle weakness, had no evidence of muscle disease on physical examination, and had negative findings on the laboratory workup for muscle disease, including levels of creatinine kinase, aspartate aminotransferase, alanine aminotransferase, and aldolase. In accordance with the limited previous literature on anti-TNF–induced DM, we performed screening for malignancy, with no significant findings.3

In conclusion, anti-TNF therapy has been a valuable addition in the treatment armamentarium for autoimmune and inflammatory disorders. Although the use of these agents is increasing, practitioners should be aware of the possibility for anti-TNF–induced autoimmune disorders, including DM. The case described herein is unique in that anti-TNF–associated disease occurred in a patient with existing arthritis since childhood, adding further evidence to support the existence of anti-TNF–induced DM, and that only cutaneous features of DM were noted with a lack of muscle involvement. All patients with skin findings suggestive of DM should undergo appropriate evaluation, including consideration of associated drug culprits, investigation for muscle and pulmonary disease, and assessment for underlying malignancy. Physicians should also use caution in rechallenging patients with anti-TNF–induced DM with another anti-TNF agent.

Accepted for Publication: May 15, 2013.

Corresponding Author: Ruth Ann Vleugels, MD, MPH, Department of Dermatology, Brigham and Women’s Hospital, Alumnae Hall, Ste 319, 41 Ave Louis Pasteur, Boston, MA 02115 (rvleugels@partners.org).

Published Online: August 28, 2013. doi:10.1001/jamadermatol.2013.5220.

Author Contributions:Study concept and design: Liu, Velez, Townsend, Vleugels.

Acquisition of data: Liu, Femia, Granter, Townsend, Vleugels.

Analysis and interpretation of data: Liu, Lam, Femia, Granter, Vleugels.

Drafting of the manuscript: Liu, Townsend, Vleugels.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Liu.

Administrative, technical, and material support: Velez, Lam, Townsend.

Study supervision: Vleugels.

Conflict of Interest Disclosures: None reported.

Additional Information: Dr Vleugels’s career has been supported by a Medical Dermatology Career Development Award from the Dermatology Foundation.

Ramos-Casals  M, Perez-Alvarez  R, Diaz-Lagares  C, Cuadrado  M-J, Khamashta  MA; BIOGEAS Study Group.  Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9(3):188-193.
PubMed   |  Link to Article
Ramos-Casals  M, Brito-Zerón  P, Soto  M-J, Cuadrado  M-J, Khamashta  MA.  Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol. 2008;22(5):847-861.
Link to Article
Klein  R, Rosenbach  M, Kim  EJ, Kim  B, Werth  VP, Dunham  J.  Tumor necrosis factor inhibitor-associated dermatomyositis. Arch Dermatol. 2010;146(7):780-784.
PubMed   |  Link to Article
Moustou  AE, Matekovits  A, Dessinioti  C, Antoniou  C, Sfikakis  PP, Stratigos  AJ.  Cutaneous side effects of anti–tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol. 2009;61(3):486-504.
PubMed   |  Link to Article
Riolo  G, Towheed  TE.  Anti–tumor necrosis factor inhibitor therapy–induced dermatomyositis and fasciitis. J Rheumatol.2012;39(1):192-194.
Brunasso  AM, Scocco  GL, Massone  C.  Dermatomyositis during adalimumab therapy for rheumatoid arthritis. J Rheumatol.2010;37(7):1549-1550.
Link to Article
Hall  HA, Zimmermann  B.  Evolution of dermatomyositis during therapy with a tumor necrosis factor α inhibitor. Arthritis Rheum. 2006;55(6):982-984.
PubMed   |  Link to Article
Ishikawa  Y, Yukawa  N, Ohmura  K,  et al.  Etanercept-induced anti-Jo-1-antibody–positive polymyositis in a patient with rheumatoid arthritis: a case report and review of the literature. Clin Rheumatol. 2010;29(5):563-566.
PubMed   |  Link to Article
Musiał  J, Undas  A, Celińska-Lowenhoff  M.  Polymyositis associated with infliximab treatment for rheumatoid arthritis. Rheumatology (Oxford).2003;42(12):1566-1568.
Link to Article
Urata  Y, Wakai  Y, Kowatari  K, Nitobe  T, Mizushima  Y.  Polymyositis associated with infliximab treatment for rheumatoid arthritis. Mod Rheumatol. 2006;16(6):410-411.
PubMed   |  Link to Article
Ishikawa  Y, Yukawa  N, Kawabata  D,  et al.  A case of antisynthetase syndrome in a rheumatoid arthritis patient with anti-PL-12 antibody following treatment with etanercept. Clin Rheumatol. 2011;30(3):429-432.
PubMed   |  Link to Article
Ishiguro  T, Takayanagi  N, Miyahara  Y, Yanagisawa  T, Sugita  Y.  Antisynthetase (anti PL-7 antibody) syndrome presenting as a skin rash and exacerbation of interstitial pneumonia during treatment for rheumatoid arthritis [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2010;48(3):240-246.
PubMed
Martínez-Cordero  E, León  DE, Ortega  LA.  Association of polymyositis with rheumatoid arthritis. Rheumatol Int. 2001;20(3):119-123.
PubMed   |  Link to Article
Nagashima  T, Minota  S.  Dermatomyositis in patients with rheumatoid arthritis during adalimumab therapy [letter]. J Rheumatol.2011;38(3):574-575.
Link to Article
Euwer  RL, Sontheimer  RD.  Amyopathic dermatomyositis (dermatomyositis siné myositis): presentation of six new cases and review of the literature. J Am Acad Dermatol. 1991;24(6, pt 1):959-966.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Facial Findings of Dermatomyositis

The patient was noted to have midfacial erythema and a heliotrope eruption of the upper eyelids.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Lateral Thigh Findings of Dermatomyositis

The patient was noted to have poikilodermatous patches and thin plaques with cutaneous erosions on the lateral thigh.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Dorsal Hand Findings of Dermatomyositis

The patient was noted to have Gottron papules (A) and periungual erythema with cuticular hypertrophy and telangiectatic vessels (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Punch Biopsy Specimen From the Inflammatory Eruption on the Patient’s Right Shoulder

Scattered lymphocytes associated with loss of the basal cell layer, apoptotic cells, and reactive squamous changes are seen at the dermal-epidermal junction (A), with bluish-gray mucin between collagen bundles throughout the dermis (B) (original magnification ×400).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Clinical Characteristics of Reported Patients Who Developed DM, PM, or AS After Anti-TNF Therapy

References

Ramos-Casals  M, Perez-Alvarez  R, Diaz-Lagares  C, Cuadrado  M-J, Khamashta  MA; BIOGEAS Study Group.  Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9(3):188-193.
PubMed   |  Link to Article
Ramos-Casals  M, Brito-Zerón  P, Soto  M-J, Cuadrado  M-J, Khamashta  MA.  Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol. 2008;22(5):847-861.
Link to Article
Klein  R, Rosenbach  M, Kim  EJ, Kim  B, Werth  VP, Dunham  J.  Tumor necrosis factor inhibitor-associated dermatomyositis. Arch Dermatol. 2010;146(7):780-784.
PubMed   |  Link to Article
Moustou  AE, Matekovits  A, Dessinioti  C, Antoniou  C, Sfikakis  PP, Stratigos  AJ.  Cutaneous side effects of anti–tumor necrosis factor biologic therapy: a clinical review. J Am Acad Dermatol. 2009;61(3):486-504.
PubMed   |  Link to Article
Riolo  G, Towheed  TE.  Anti–tumor necrosis factor inhibitor therapy–induced dermatomyositis and fasciitis. J Rheumatol.2012;39(1):192-194.
Brunasso  AM, Scocco  GL, Massone  C.  Dermatomyositis during adalimumab therapy for rheumatoid arthritis. J Rheumatol.2010;37(7):1549-1550.
Link to Article
Hall  HA, Zimmermann  B.  Evolution of dermatomyositis during therapy with a tumor necrosis factor α inhibitor. Arthritis Rheum. 2006;55(6):982-984.
PubMed   |  Link to Article
Ishikawa  Y, Yukawa  N, Ohmura  K,  et al.  Etanercept-induced anti-Jo-1-antibody–positive polymyositis in a patient with rheumatoid arthritis: a case report and review of the literature. Clin Rheumatol. 2010;29(5):563-566.
PubMed   |  Link to Article
Musiał  J, Undas  A, Celińska-Lowenhoff  M.  Polymyositis associated with infliximab treatment for rheumatoid arthritis. Rheumatology (Oxford).2003;42(12):1566-1568.
Link to Article
Urata  Y, Wakai  Y, Kowatari  K, Nitobe  T, Mizushima  Y.  Polymyositis associated with infliximab treatment for rheumatoid arthritis. Mod Rheumatol. 2006;16(6):410-411.
PubMed   |  Link to Article
Ishikawa  Y, Yukawa  N, Kawabata  D,  et al.  A case of antisynthetase syndrome in a rheumatoid arthritis patient with anti-PL-12 antibody following treatment with etanercept. Clin Rheumatol. 2011;30(3):429-432.
PubMed   |  Link to Article
Ishiguro  T, Takayanagi  N, Miyahara  Y, Yanagisawa  T, Sugita  Y.  Antisynthetase (anti PL-7 antibody) syndrome presenting as a skin rash and exacerbation of interstitial pneumonia during treatment for rheumatoid arthritis [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2010;48(3):240-246.
PubMed
Martínez-Cordero  E, León  DE, Ortega  LA.  Association of polymyositis with rheumatoid arthritis. Rheumatol Int. 2001;20(3):119-123.
PubMed   |  Link to Article
Nagashima  T, Minota  S.  Dermatomyositis in patients with rheumatoid arthritis during adalimumab therapy [letter]. J Rheumatol.2011;38(3):574-575.
Link to Article
Euwer  RL, Sontheimer  RD.  Amyopathic dermatomyositis (dermatomyositis siné myositis): presentation of six new cases and review of the literature. J Am Acad Dermatol. 1991;24(6, pt 1):959-966.
PubMed   |  Link to Article

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