Clinical research in rheumatology 2012–2013: methodologic considerations in study design Allan C. Gelber
There are many circumstances in the course of a regular week in which a rheumatologist evaluating a new, or established, patient poses a key question to further understand the relationship of a symptom, or of a finding on physical examination, to the leading consideration on the differential diagnosis list. One might similarly ponder the predictive value of a clinical or laboratory marker in relation to the outcome of most concern to the patient, his/her family, and to the physician alike. Were the patient to present with both Raynaud’s phenomenon and proximal weakness, the treating physician might contemplate the possible coexistence of evolving systemic sclerosis (scleroderma) with features of on an inflammatory myopathy. Alternately, if the patient had an established diagnosis of systemic lupus erythematosus with multiple recurrent episodes of sustained inflammation, the rheumatologist might speculate on the risk borne by the patient and consider what clinical and/or laboratory parameters might predict an increase in risk to develop a lymphoproliferative disorder. In a similar vein, what if the patient with established lupus returned in follow-up with the announcement of a recently positive pregnancy test and prompted the rheumatologist to address what ongoing medications ought be promptly discontinued, versus those whose use could be sustained, with reasonable safety, over the duration of the pregnancy while contemplating the potential impact on the stability of the pregnancy and to the viability of the maturing fetus? Certainly, a most common scenario is the patient with known osteoarthritis of the knee who presents with increasingly refractory symptoms and impairment in routine leisure time activities, or a young man with persistent inflammatory low back pain in the context of a well established diagnosis of ankylosing spondylitis. The former patient might inquire if arthroscopic meniscectomy surgery is advisable, whereas the latter might query if intensification of drug therapy to a biologic agent is advisable. Further, the rheumatologist might further ponder which clinical
or serologic parameters presage a heightened risk of mortality among the patients with scleroderma in the practice, for whom more frequent care and increased vigilance might favorably alter the course of disease. It is just these sorts of questions, quite relevant to direct patient care, yet difficult, if not impossible to answer at the level of individual patients in a single practice, that stimulate compelling clinical research endeavors. Moreover, perusal of the rheumatology literature over the last year highlights several instructive reports, which illuminate just this sort of queries [1–6]. In this issue of Current Opinion in Rheumatology, six articles delve into recent developments in the areas of osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and scleroderma. Each review is authored by an expert(s) in the field, and each emphasizes the methodologic considerations influenced by study design. Consequently, strengths and limitations of these new studies from 2012 to 2013, in the context of prior reports in these disease areas, are systematically presented. Thus, distinct from the challenge in making a new diagnosis of lupus and initiation of a course of therapy that reasonably matches the intensity of the disease flare with the potential toxicity profile of the medications selected, there are many additional challenges to the rheumatologists in the care of patients with an established diagnosis of lupus. These include what degree of vigilance is warranted regarding a heightened long-term risk to develop lymphoma? Similarly, how should medical management be impacted when a woman of child-bearing age with established lupus is contemplating a Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to Allan C. Gelber, MD, MPH, PhD, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Bldg. Center Tower, Suite 4100 Baltimore, MD 21224, USA. Tel: +1 410 550 2018; fax: +1 410 550 2072; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:109–110 DOI:10.1097/BOR.0000000000000039
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planned pregnancy? To address these clinically relevant scenarios, Petri and Bichile critically evaluate the former topic, whereas Peart and Clowse address the latter concerns. In the context of scleroderma, there are similarly clinical scenarios that stand to benefit from well conducted studies, to illuminate distinct phenotypic subsets of disease and to identify the predictors of outcome. In particular, Paik, Mammen, Wigley, and Gelber focus their review on scleroderma myopathy, how to identify this condition, and to manage this condition including related prognostic factors. In contrast, Nikpour and Baron review predictors associated with a heightened risk of mortality in scleroderma, a disorder in which susceptibility to critical organ system dysfunction can occur early in the course of disease, and may lead to particularly dire outcomes, including threatened survival, at a greater rate than in most other inflammatory rheumatic disorders. In the context of knee osteoarthritis and ankylosing spondylitis, there are ongoing vexing challenges in patient management. A longstanding question persists, after more than a decade of reports, regarding the beneficial impact, or lack thereof, of surgical intervention for patients with moderate osteoarthritic knee involvement. Stated differently, there is no question that for decades total joint replacement has been a major therapeutic advance for those with advanced, degenerative arthritis refractory to medical therapy. But, in the context of the patient with less severe disease, does arthroscopic meniscectomy confer benefit over a nonsurgical approach, particularly a physical therapy and active exercise alternative. Buchbinder, Richards, and Harris review this issue. Finally, in the context of ankylosing spondylitis, Louie and Ward focus on the therapeutic benefit of biologic therapy, particularly inhibitors of tumor necrosis factor alpha, and on NSAID therapy, on spinal disease involvement. Thus, whereas NSAID and biologic agents are efficacious at control of joint pain and stiffness and ameliorate functional status
in affected patients, a key issue over the medium long term is whether radiographic progression of disease can be halted, or slowed, a fundamental outcome of keen interest, in the long-term management of these patients. What unifies these review articles is the importance of integrating the fundamentals of study design during interpretation of findings from clinical research reports. Consequently, emphasis on the strengths and weaknesses of case series, case–control, cohort, and randomized clinical studies serve as a central theme in this issue of the Journal and are emphasized in the titles of each of article. Thus, whether the reader is a rheumatologist primarily engaged in patient care or is primarily a clinical investigator engaged in the research enterprise to further define the cause, course, and outcomes of persons afflicted with arthritis, musculoskeletal, and rheumatic disorders, both stand to benefit from the disorders and themes examined in this issue. Acknowledgements None. Conflicts of interest There are no conflicts of interest relevant to this article.
Bernatsky S, Ramsey-Goldman R, Joseph L, et al. Ly Lymphoma risk in systemic lupus: effects of disease activity versus treatment. Ann Rheum Dis 2014; 73:138–142. Katz JN, Brophy RH, Chaisson CE, et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis. N Engl J Med 2013; 368:1675–1684. Clowse ME, Wallace DJ, Weisman M, et al. Predictors of preterm birth in patients with mild systemic lupus erythematosus. Ann Rheum Dis 2013; 72:1536–1539. Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford) 2013; 52:155–160. Braun J, Baraliakos X, Hermann KG, et al. The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis 2013. [Epub ahead of print] Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis 2013; 72:1217–1220.
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