Dear Editor,

We were interested to read the article by Linn-Rasker and colleagues who report that smoking is a risk factor for anti-cyclic-citrullinated (anti-CCP) antibodies only in RA patients that carry HLA-DRB1 shared epitope (SE) alleles.[1] They claim that an interaction is found between tobacco exposure (TE) and carriage of the SE which leads to anti-CCP production in RA. They find a similar effect for presence of rheumatoid factor (RF), but suggest that the interaction is primarily with the anti- CCP antibody response. Although an attractive hypothesis, our analysis of the data presented does not agree with their interpretation.

We have used the data provided in Table 2 to investigate the independent and combined affects of RF, TE and SE (independent variables) on the presence of anti-CCP antibodies (dependent variable) using multivariate logistic regression models. Firstly we examined for evidence of interaction. In a model which includes TE only there is significant association with the presence of anti-CCP (OR 1.6, 95% CI 1.01 – 2.6, p = 0.04). Addition of SE to the model indicates that TE and SE are independently associated with anti-CCP since both are significant (OR 1.7, 95% CI 1.04 – 2.8, p = 0.03, and OR 3.3, 95% CI 2.01 – 5.6, p <0.0001, respectively). However, if the interaction term (product of TE and SE) is added into the model together with the main effects (TE and SE separately) there is no association between the interaction term and anti-CCP (p = 0.2). This does not rule out the possibility of an additive effect of TE and SE but argues against a multiplicative interaction. In a similar way we have previously shown that RF production is associated with an additive, but not multiplicative interaction between smoking and the HLA- DRB1*0401 SE allele.[2]

We have also investigated more closely the influence of RF on the association between TE and anti-CCP. Analysis of SE+ patients only in a logistic regression model without adjustment for RF suggests that TE is associated with the presence of anti-CCP (OR 2.1, 95% CI 1.2 – 3.9, p = 0.016). However inclusion of RF as well as TE in the same model reveals a strong association with RF (OR 16.1, 95% CI 7.6 – 34.1, p <0.00001), while the association with TE loses significance (OR 1.7, 95% CI 0.9 – 3.6, p = 0.17).

Our analyses indicate that the apparent association between TE and anti-CCP can be explained by the confounding association of RF with smoking. The dominant association of RF with anti-CCP can be seen in the last section of Table 2 where non smokers carry as much risk of developing anti-CCP (OR 3.83) as smokers (OR 3.86) if they are positive for both the SE and RF. Further examination of the data in Table 2 also shows that, with or without tobacco exposure, SE negative patients who are RF positive actually have a higher risk of developing anti-CCP antibodies than SE positive smokers who are RF negative (68% v 43.3%, OR 2.7 and 66.7% v 43.3%, OR 2.5, respectively).

Our analyses of these data are consistent with a previous preliminary report on the association of RF and SE, but not smoking, with anti-CCP.[3] This was a study on 271 RA patients in which we also examined the association of HLA-DRB1*0401 with the presence of anti-CCP. Our results showed that patients who were smokers were more likely to be positive for anti-CCP antibodies than those who had never smoked. However, inclusion of RF, together with smoking status as independent variables in logistic regression analyses caused loss of significance between smoking and anti- CCP, while RF remained significantly associated (OR 6.2, 95% CI 1.9 -10.2, p<_0.0001. additional="additional" inclusion="inclusion" of="of" hla-drb10401="hla-drb10401" status="status" in="in" a="a" logistic="logistic" regression="regression" model="model" demonstrated="demonstrated" that="that" this="this" was="was" also="also" strongly="strongly" associated="associated" with="with" anti-ccp="anti-ccp" or="or" _4.7="_4.7" _95="_95" ci="ci" _1.9="_1.9" _-11.4="_-11.4" p="p" independent="independent" rf.="rf." these="these" data="data" indicate="indicate" although="although" ra="ra" smokers="smokers" are="are" more="more" likely="likely" to="to" be="be" positive="positive" for="for" appears="appears" primarily="primarily" due="due" an="an" association="association" rf="rf" patients="patients" who="who" smoke.="smoke."/> Derek L. Mattey
Staffordshire Rheumatology Centre
University Hospital of North Staffordshire
Stoke-on-Trent
Staffordshire
UK
ST6 7AG

David Hutchinson
Royal Cornwall Hospital
Truro
Cornwall
UK
TR1 3LJ

Correspondence to Dr DL Mattey. d.l.mattey{at}keele.ac.uk

References

1. Linn-Rasker SP, van der Helm-van Mil AHM, Van Gaalen FA, Kloppenburg M, de Vries R, LE Cessie S, et al. Smoking is a risk factor for anti-CCP antibodies only in RA patients that carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis published online 13 Jul 2005;doi:10.1136/ard.2005.041079.

2. Mattey DL, Dawes PT, Clarke S, Fisher J, Brownfield A, Thomson W, Hajeer AH, Ollier WER. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheum 2002;47:403-407.

3. Mattey DL, Nixon NB, Hutchinson D. Rheumatoid factor and HLA- DRB1*0401, but not cigarette smoking, are independently associated with antibodies to cyclic citrullinated peptides in rheumatoid arthritis. Rheumatology 2005;44(Suppl):i100.

Dear Editor,

I would like to offer some comments on the paper: Evaluation of clinically relevant changes in patient-reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement by Florence Tubach, et al.

The authors did a good job of collecting a mass of data and deriving a delta for the Minimal Clinically Important Improvement for the three core efficacy variables in osteoarthritis.

The result is, however, not quite convenient because three deltas are derived depending on the value of the baseline variable. This is awkward - as e.g. also the definition of three relevant difference delts for proportion of responders as given in the 80's by the FDA. I wonder whether one could derive a smooth, constant delta on another scale. The floor effect of the scale (0 - no pain) and the decrease of pain which often follows the shape of a proportional decrease suggest that a percentage scale of decrease or difference in logarithms might be easier to handle and also more appropriate for the data. (Andiometrists are very happy with their dB scale for andiometry perception.)

I would appreciate the authors doing some additional work to obtain a constant delta. A pre-post scattergram of BAS values would be a good starting point. (See, for example, Chambers, Cleveland, Kleiner, Tukev, Graphical Methods for Data Analysis, Duxbury Press, Boston).

Dear Editor,

The article, "Circadian Rhythms in RA" postulates a dynamic equilibrium between melatonin and cortisol as at least part of the etiology of rheumatoid arthritis. The authors note that the clinical symptoms of pain and stiffness seem to peak around 5:00 o'clock in the morning and that this coincides with the diurnal rhythms of melatonin and cortisol. Because melatonin enhances inflammatory cytokine and nitric oxide production, they suggest that inhibitors of melatonin or melatonin antagonists should be considered as possible therapeutic tools.[1]

Another variable that changes throughout the sleep cycle is regional cerebral blood flow. The lowest absolute cerebral blood flow values occur during REM sleep towards the end of the sleep cycle.[2] Nitric oxide release causes the depressed cerebral blood flow. It can persist for several hours.[3] Nitric oxide synthase inhibition abolishes sleep-wake differences in cerebral circulation.[4]

Nitric oxide release correlates with disease activity in patients with rheumatoid arthritis.[5] Additionally, nitric oxide synthase inhibitors are currently under consideration for the treatment of the pain associated with rheumatoid arthritis.[6]

On the other hand, melatonin and its precursors scavenge nitric oxide.[7] Thus, it would seem that any therapeutic benefit achieved by suppressing melatonin would be reduced, if not eliminated, by the loss of the nitric oxygen scavenging ability of endogenous melatonin production on the nitric oxide released during the sleep cycle.

References

1. Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli A. Circadian Rhythms in RA. Ann. Rheum. Dis 2003; 63:593-596.

2. Braun A, Balkin T, Wesenten N, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H2 (15) O PET study. Brain, 120:1173- 97.

3. Lauritzen M. Cerebral blood flow in migraine and cortical spreading depression. Acta Neurol Scand Suppl.1987; 113:1-40.

4. Zoccoli G, Grant D, Wild J. et al. Nitric oxide inhibition abolishes sleep-wake differences in cerebral circulation 2001. Am J Physiol Heart Circ Physiol, 280 Issue 6, H2598-2606.

5. St Clair EW, Wilkinson WE, Lang T. et al. Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients. J Exp Med. 1996 Sep 1; 184(3):1173-8.

6. Nakamura H, Ueki Y, Sakito S, Matsumoto K. et al. Clinical effects of actarit in rheumatoid arthritis: improvement of early disease activity mediated by reduction of serum concentrations of nitric oxide. Clin Exp Rheumatol. 2000; 18(4):445-50.

7. Noda Y, Mori A, Liburdy R. et al. Melatonin and its precursors scavenge nitric oxide. J Pineal Res. 1999; 27(3):159-63.

Dear Editor,

We read with great interest the recent paper by Pappas et al. [1] and we would like to add some considerations about brucellosis as a cause of carpal tunnel syndrome (CTS).

Brucellosis has been an endemic disease in Castilla y León (Spain) until the 1990’s. In 1992 we reported a series of 44 cases of brucellosis with musculoskeletal manifestations diagnosed in the division of rheumatology of the Hospital General Yagüe of Burgos between 1988 and 1991 [2]. Seven of them (15.9%) had CTS, confirmed by nerve conduction studies, concurrently with the clinical picture of brucellosis. They were five males and two women. Four of the patients were stockbreeders, one was a butcher, another was slaughterhouse worker, and a last one used to drink not-pasteurized milk. The time from the beginning of the symptoms to the diagnosis of brucellosis was less than three months in five of the patients and more than a year in the other two. Four patients had bilateral CTS. In one case, CTS was the only manifestation of brucellosis.

Three patients had flexor tenosynovitis and/or wrist arthritis considered as the cause of the CTS; in the other four, with not evident local inflammation, the suggested cause of compression of the median nerve could be a subclinic joint or tendinous affectation or a peripheral neuropathy due to brucellosis. Two patients were submitted to carpal surgical decompression of the median nerve. In both cases there was a significant infiltrate of lymphocytes and plasma cells, with microgranulomas in one. Antibiotic treatment for brucellosis was effective in all of the patients except the one with the more chronic evolution, who sustained a nervous residual damage in spite of antibiotic and surgical treatment.

Our belief is that CTS associated with brucellosis could be more frequent than one would found reported in the literature, and sometimes can be the only clinical manifestation of brucellosis. As Pappas et al., we emphasize that brucellosis should be included in differential diagnosis of CST in countries where the disease is endemic. Furthermore, this disease has to be considered in those cases in which the pathological study shows a dense infiltrate of lymphocytes and plasma cells and/or microgranulomas.

B Alvarez Lario, JL Alonso, J Macarrón*
Division of Rheumatology and Neurology*
Hospital General Yagüe. Burgos. Spain.

References

1. Pappas G, Markoula S, Sitaridis S, Akritidis N, Tsianos E. Brucellosis as a cause of carpal tunnel syndrome. Ann Rheum Dis 2005; 64: 792-793.

2. Alvarez Lario B, Alonso JL, Alegre J, Vidal J. Síndrome del túnel carpiano asociado a brucelosis. Rev Esp Reumatol 1992; 17: 185-186.