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A series of substituted sulfonanilide analogs were prepared and evaluated as novel potent inhibitors of SH2 domaincontaining inositol polyphosphate 5′-phosphatase 2 (SHIP2). SHIP2 has been shown to be a new attractive target for the treatment of insulin resistance in type 2 diabetes mellitus (T2D), which can lead to life-threatening diabetic kidney disease (DKD). Amongst the synthesized compounds, the two most promising candidates, 10 and 11, inhibited SHIP2 significantly. Additionally, these compounds induced Akt activation in a dose-dependent manner, increased the presence of glucose transporter 4 at the plasma membrane, and enhanced glucose uptake in cultured myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.

Objective To explore the impact of an early treatment response on maintenance of work capacity in patients with early, active rheumatoid arthritis (RA). Methods In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomized to receive either a combination of disease-modifying antirheumatic drugs (DMARDs) with prednisolone or a single DMARD with or without prednisolone for 2 years. Treatment responses were evaluated according to the American College of Rheumatology (ACR) criteria. After a 5-year followup, the cumulative number of days of sick leave and RA-related permanent work disability was calculated for each of the 162 patients who were available for the active work force at baseline. Results Of the 159 patients assessed at 6 months, 29 were in clinical remission, 66 achieved an ACR50 response but not remission, 29 achieved an ACR20 response but not an ACR50 response, and 35 failed to achieve an ACR20 response. In these 4 groups, the median numbers of work disability days per patient-year from 6 months through 60 months of followup were 0 (interquartile range [IQR] 0–3), 4 (IQR 0–131), 16 (IQR 0–170), and 352 (16–365), respectively (P < 0.001). Pairwise multiple comparisons showed a statistically significant difference between all groups except the ACR50 and ACR20 groups. At 12 months, 30 patients were in remission. None of the 44 patients in remission at 6 or 12 months became permanently work disabled over the 5-year followup, as compared with 15 patients in the ACR50 group (23%), 6 in the ACR20 group (21%), and 19 without an ACR20 response at 6 months (56%). Conclusion Prompt induction of remission translates into maintenance of work capacity. At 6 months, an ACR50 response is no better than an ACR20 response with regard to future productivity, while failure to achieve an ACR20 response carries a high risk for work disability.

Summary Background The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis. Methods 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat. Findings 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0·011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0·003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0·028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0·058) had clinically improved. The frequencies of adverse events were similar in both treatment groups. Interpretation Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.