Daniel J McCarty, MD: A Giant of Rheumatology.

There is no doubt that Dr Daniel J McCarty warrants inclusion among the giants of rheumatology. He has made major contributions to both clinical and scientific knowledge in our field, and his impact has been long-lasting and paradigm shifting. He is perhaps best known for his pioneering work in crystal arthritis, but as an astute clinician, he is also responsible for describing several other novel rheumatic conditions and developing innovative treatment protocols.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study.

OBJECTIVES: PHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc). METHODS: "At-risk" pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40 mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan-Meier estimate of time to PH diagnosis. RESULTS: A total of 251 "at-risk" subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 ± 1.2 years. The mean age at entry was 56.7 ± 11.0 and disease duration was 9.9 ± 8.7 years. Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the "at-risk" and new PH groups. Using Kaplan-Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than "at-risk" PAH group. CONCLUSIONS: A low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.

Items for developing revised classification criteria in systemic sclerosis: Results of a consensus exercise.

OBJECTIVE: Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT). METHODS: Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale. RESULTS: In round 1, 106 experts rated the 168 items. Those with a median score of <4 were removed, resulting in a list of 102 items. In round 2, the items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n = 16), resulting in 23 items. In round 3, SSc experts (n = 26) then individually scored each of the 23 items in a last Delphi round using an appropriateness score (1-9) and ranking their 10 most appropriate items for the classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, and Raynaud's phenomenon ranked highest in the final list that also included items indicating internal organ involvement. CONCLUSION: The Delphi exercise and NGT resulted in a set of 23 items for the classification of SSc that will be assessed for their discriminative properties in a prospective study.

Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 microg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 microg/kg/day and 25 microg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc. METHODS: Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 microg/kg/day or 25 microg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28. RESULTS: The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo. CONCLUSION: Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy.

BACKGROUND: Immunomodulator therapy with the purine analogs azathioprine and 6-mercaptopurine (6-MP), is efficacious in the treatment of moderate to severe Crohn's disease (CD), but is not tolerated by a significant minority of patients. The pyrimidine analog, leflunomide, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) patients. Because established RA immunomodulator agents may demonstrate success in the treatment of CD, we reviewed our clinical open-label experience with leflunomide in a refractory CD population. GOALS Assess the effect of leflunomide 20 mg daily, on disease activity, steroid requirement and serologic measures of inflammatory activity in our series of CD patients intolerant to azathioprine/6-MP. STUDY: CD patients intolerant of azathioprine/6-MP were offered leflunomide treatment. The Harvey-Bradshaw (H-B) disease activity index, global assessment, serologic parameters and ability to taper corticosteroids of those who accepted were retrospectively assessed. RESULTS: Leflunomide was well tolerated and resulted in a significant reduction in the H-B score, global assessment and serologic parameters in 8/12 patients. Average follow-up was 38 weeks and a majority of steroid-dependent patients were able to successfully taper following leflunomide initiation. CONCLUSIONS: Our case series demonstrates that the pyrimidine analog leflunomide may be effective for treating moderate to severe CD patients intolerant to standard immunomodulator therapy and warrants further investigation in a randomized controlled trial.