Objective. To determine the efficacy of combined spa-exercise therapy in addition to standard treatment with drugs and weekly group physical therapy in patients with ankylosing spondylitis (AS). Methods. A total of 120 Dutch outpatients with AS were randomly allocated into 3 groups of 40 patients each. Group 1 (mean age 48 ؎ 10 years; male:female ratio 25:15) was treated in a spa resort in Bad Hofgastein, Austria; group 2 (mean age 49 ؎ 9 years; male:female ratio 28:12) in a spa resort in Arcen, The Netherlands. The control group (mean age 48 ؎ 10 years; male:female ratio 34:6) stayed at home and continued their usual drug treatment and weekly group physical therapy during the intervention weeks. Standardized spa-exercise therapy of 3 weeks duration consisted of group physical exercises, walking, correction therapy (lying supine on a bed), hydrotherapy, sports, and visits to either the Gasteiner Heilstollen (Austria) or sauna (Netherlands). After spa-exercise therapy all patients followed weekly group physical therapy for another 37 weeks. Primary outcomes were functional ability, patient's global well-being, pain, and duration of morning stiffness, aggregated in a pooled index of change (PIC). Results. Analysis of variance showed a statistically significant time-effect (P < 0.001) and time-by-treatment interaction (P ‫؍‬ 0.004), indicating that the 3 groups differed over time with respect to the course of the PIC. Four weeks after start of spa-exercise therapy, the mean difference in PIC between group 1 and controls was 0.49 (95% confidence interval [CI] 0.16 -0.82, P ‫؍‬ 0.004) and between group 2 and controls was 0.46 (95% CI 0.15-0.78, P ‫؍‬ 0.005). At 16 weeks, the difference between group 1 and controls was 0.63 (95% CI 0.23-1.02, P ‫؍‬ 0.002) and between group 2 and controls was 0.34 (95% CI ؊ 0.05-0.73; P ‫؍‬ 0.086). At 28 and 40 weeks, more improvement was found for group 1 compared with controls (P ‫؍‬ 0.012 and P ‫؍‬ 0.062, respectively) but not for group 2 compared with controls. Conclusion.In patients with AS, a 3-week course of combined spa-exercise therapy, in addition to drug treatment and weekly group physical therapy alone, provides beneficial effects. These beneficial effects may last for at least 40 weeks.

The existing trials suggest a positive effect of radon therapy on pain in rheumatic diseases. With respect to the potential clinical effect and given the increasing public interest in radon therapy, there is an urgent need for further randomized controlled clinical investigations with long-term follow-up.

These results demonstrate a significant increase in circulating TGF-beta1 in patients with AS after the combined spa-exercise therapy in Badgastein. The results also provide evidence for a biological response to speleotherapy and suggest that TGF-beta, through its antiinflammatory function, may play a role in this response.

Digital clubbing is the most prominent feature in primary (PHO) and secondary (pulmonary) hypertrophic osteoarthropathy (HO). Homozygous and compound heterozygous germline mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene encoding the major prostaglandin PGE2 catabolizing enzyme have been recently described in familial PHO cases. Elevated prostaglandin levels in affected individuals with cytokine-mediated tissue remodelling and vascular stimulation may underlie PHO and associated features as hyperhidrosis, acroosteolysis, pachyderma, periostosis and arthritis. We present clinical and biochemical data of three unrelated PHO families with HPGD mutations. The truncating mutation c.175_176del was found in two of our families and in one of the recently described pedigrees, all of European origin. We present evidence that c.175_176del is a recurrent mutation rather than an ancient founder allele. Two novel heterozygous HPGD mutations, the nonsense mutation c.118G>T (p.Glu40X) and the missense mutation c.563C>T (p.Thr188Ile), could be identified in a third family. We postulate that all HPGD mutations constitute loss-of-function alleles due to protein truncation or missense changes that affect hydrogen bonds lining the 15-PGDH enzyme reaction cavity. Elevated prostaglandin levels may give rise to use of non-steroidal anti-inflammatory drugs; however, therapeutic strategies have not been reported to date. Naproxen treatment in one of our mutation-positive patients resulted in alleviation of pain caused by periostosis and arthritis as well as reduction in substantially elevated prostaglandin levels, while no significant effects on digital clubbing, hyperhidrosis and pachyderma were observed. Further experience with nonsteroidal anti-inflammatory drugs in PHO is awaited.

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