Sindhu R. Johnson

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Thrombotic arteriopathy and anticoagulation in pulmonary hypertension.

The role of thrombotic arteriopathy in the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH) and the use of anticoagulants in the treatment of IPAH are currently controversial issues. This article reviews the evidence for a role of vascular thrombosis in the pathophysiology of IPAH. There is sufficient biological rationale to support the notion that thrombotic arteriopathy is an important pathophysiologic feature of pulmonary arterial hypertension (PAH) and that its progression materially contributes to disease progression. To date, the data from observational studies suggest that anticoagulation with warfarin is an effective intervention in patients with IPAH. Its efficacy in other causes of PAH remains speculative.

Predictors for remission in rheumatoid arthritis patients: A systematic review.

To summarize the potential predictors of remission in patients with rheumatoid arthritis (RA).

Distinctions between diagnostic and classification criteria

Rheumatologists face unique challenges in discriminating between rheumatologic and non-rheumatologic disorders with similar manifestations, and in discriminating among rheumatologic disorders with shared features. The majority of rheumatic diseases are multisystem disorders with poorly understood etiology; they tend to be heterogeneous in their presentation, course, and outcome, and do not have a single clinical, laboratory, pathological, or radiological feature that could serve as a “gold standard” in support of diagnosis and/or classification. Thus, the development of criteria for use in routine clinical care and in clinical research has been an important focus in rheumatology. Improved understanding of disease pathogenesis and new diagnostic tools have led to reexamination of existing classification and diagnostic criteria with updated classification criteria for some diseases being endorsed recently (1, 2). The American College of Rheumatology (ACR) Subcommittee on Classification and Response Criteria is responsible for guiding the development and validation of new classification and response criteria that are eventually considered for ACR endorsement. This includes review of proposals for the development of new criteria sets and providing the ACR leadership with recommendations for development and approval of new classification and response criteria sets (1, 3–5). The Subcommittee has previously published a guidance paper for the development of classification and response criteria (6). This prior work has provided details about the rationale for the ACR’s position on classification criteria, but clarification around the issue of diagnostic criteria was lacking. Indeed, the ACR endorsed preliminary diagnostic criteria for fibromyalgia (7) in 2010, which prompted discussions about whether the Subcommittee should also support the development and ACR endorsement of diagnostic criteria, in addition to that of classification and response criteria. The primary objectives of this current article, by former and current members of the Subcommittee on Classification and Response Criteria, are to compare diagnostic and classification criteria, using specific examples from the published literature, and to clarify the ACR’s position on both types of criteria.

Pulmonary hypertension in systemic lupus

Pulmonary arterial hypertension (PAH) has devastating consequences in the rheumatic diseases; however, the prevalence in lupus is not well delineated. We searched the University of Toronto lupus database to ascertain the first echocardiogram ordered at their physician’s discretion between 1995 and 2002. We reviewed the echocardiogram reports for right ventricular systolic pressure (RVSP), valvular disease, and atrial and ventricular function. The PAH was defined as RVSP ≥40 mmHg. Patients were divided into three groups: RVSP ≥40 mmHg, RVSP 1/4 30-39 mmHg and RVSP, 30 mmHg. We analysed potential associations between presence of PAH and lupus including disease activity, organ involvement and anticardiolipin antibodies, both at the time of and any time prior to echocardiography. In total, 129 patients underwent echocardiography. Nine patients’ echocardiogramswere not obtainable, and three patients were excluded from analysis, as their visit was more than six months from the date of echocardiography. Sixteen patients (14%) had RVSP ≥40 mmHg, 43 (37%) patients had RVSP of 30-39, and 60 (51%) patients had RVSP, 30 mmHg. There was no statistical difference in disease activity, organ involvement or serology among all three groups. In conclusion, the prevalence of PAH (RVSP ≥40 mmHg) on first echocardiogram ordered at physician discretion in our cohort was 14%. An RVSP of 30-39 mmHg was found in 37% of patients. Although abnormal, the clinical significance of this finding is unknown. Disease activity, organ involvement and anti-cardiolipin antibodies were not associated with PAH. Further research is needed to identify the mechanism, response to immunosuppression and impact on quality of life in these patients.

Validation of potential classification criteria for systemic sclerosis.

Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated jointly by the American College of Rheumatology and European League Against Rheumatism. Potential items for classification were reduced to 23 using Delphi and nominal group techniques. We evaluated the face, discriminant, and construct validity of the items to be further studied as potential criteria.

Factors that prognosticate mortality in idiopathic pulmonary arterial hypertension: a systematic review of the literature.

RATIONALE There is a lack of consensus on factors that predict mortality in idiopathic pulmonary arterial hypertension (IPAH). Tests that can accurately predict prognosis are needed to guide treatment and counsel patients. METHODS We conducted a systematic review to identify factors that prognosticate mortality in IPAH. Study design, cohort size, comparison method, measured value, and statistical significance was extracted for eight pre-selected parameters [pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), cardiac output, right ventricular end diastolic pressure, functional class, 6 min walk distance (6MWD), and diffusing capacity of carbon monoxide]. RESULTS 107 factors have been associated with mortality in IPAH. A reproducible predictive association with mortality was demonstrated for only 10 factors: functional class (14 studies), heart rate (10 studies), 6MWD (8 studies), pericardial effusion (5 studies), mPAP (10 studies), mRAP (17 studies), cardiac index (13 studies), stroke volume index (4 studies), PVR (10 studies), mixed venous PaO(2) or saturations (4 studies). Of the 8 factors chosen for detailed evaluation, there were at least half as many studies that evaluated the variable and did not find an association with mortality compared to those that did. CONCLUSIONS There is a large body of literature describing numerous factors that predict mortality in IPAH. Most factors have been assessed in very few studies. There are conflicting reports on the prognostic value of many factors. These discrepancies highlight the need to evaluate the literature in total when considering the utility of variables as prognostic factors in IPAH.

Shifting Our Thinking About Uncommon Disease Trials: The Case of Methotrexate in Scleroderma

Objective. Randomized trials for uncommon diseases suffer from methodological challenges: difficulty in recruiting sufficient numbers of patients and low power to detect important treatment effects. Using traditional (frequentist) analysis, p values > 0.05 mean investigators are unable to reject the null hypothesis (of no treatment effect). The medical community often labels trials with p values > 0.05 as “negative.” Our study demonstrates how Bayesian analysis conveys more relevant information to clinicians — using the example of methotrexate (MTX) in systemic sclerosis (SSc). Methods. Data from 71 patients with diffuse SSc (n = 35 MTX, n = 36 placebo) in the trial were reanalyzed using Bayesian models. We examined 3 primary outcomes: modified Rodnan skin score (MRSS), University of California Los Angeles (UCLA) skin score, and physician global assessment of overall disease activity. Using noninformative prior probability distributions, the probability of beneficial treatment effects for each outcome and the probability of simultaneous benefit in outcomes were computed. Results. The probability that treatment with MTX results in better mean outcomes than placebo was 94% for MRSS, 96% for UCLA skin score, and 88% for physician global assessment. There was 96% probability that at least 2 of 3 primary outcomes were better on treatment. Conclusion. Bayesian analysis of uncommon disease trials allows for more flexible and clinically relevant interpretations of the data. From the trial data, clinicians can infer that MTX has a high probability of beneficial effects on skin score and global assessment.

Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the international scleroderma renal crisis survey

OBJECTIVE To determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC. METHODS Prospective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC. RESULTS A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p < 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p = 0.09 after post-hoc adjustment for pre-existing hypertension). CONCLUSION Overall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings.