We read with interest the case report by Denschlag et al. [1]. In
addition, von Lilienfield-Toal et al. also recently described the
presentation of adult onset Still’s disease associated with occult breast
malignancy [2]. These case reports remind us that rheumatic symptoms may
precede the diagnosis of an underlying neoplasm. We recently observed an atypical presentation of scleroderma associated wit...
We read with interest the case report by Denschlag et al. [1]. In
addition, von Lilienfield-Toal et al. also recently described the
presentation of adult onset Still’s disease associated with occult breast
malignancy [2]. These case reports remind us that rheumatic symptoms may
precede the diagnosis of an underlying neoplasm. We recently observed an atypical presentation of scleroderma associated with pseudomyxoma peritonei, a rare tumour of appendiceal or ovarian origin.
A 50-year old female presented with a two-year history of
intermittent right iliac fossa pain and weight loss. Recent laparoscopy and extensive radiological investigations had identified no explanation. In addition she described new onset skin photosensitivity, Raynauds phenomenon and acute dyspnoea on exertion which was diagnosed as pleuro-pericardial serositis on high resolution computed tomography. Antinuclear
antibodies were positive, titre 1:640 (speckled pattern). IgM anti-cardiolipin antibodies were positive (46 MPLU/ml) on one occasion only but
IgG antibodies were negative as was lupus anticoagulant (she had a history
of six first trimester miscarriages). Systemic lupus erythematosus was
diagnosed and appropriate therapy commenced.
Five months later she felt skin tightness over her hands and
complained of pruritus, indigestion and arthralgia. Clinical examination
revealed scleroderma extending to the elbows and involving the neck and face, with digital ulcers and a nail bed vasculitic lesion. Skin biopsy was consistent with scleroderma. Just two months later, the patient
developed a recurrence of the right iliac fossa pain now associated with bleeding per vagina. Ultrasound revealed a 16 weeks’ size pelvic mass of ovarian origin and she underwent surgery. Histological examination was
consistent with pseudomyxoma peritonei. She is currently undergoing appropriate treatment for this tumour.
This tumour could have caused the initial presentation with weight
loss and abdominal pain, and the close temporal relationship between the
appearance of the tumour and the features initially of a lupus like
disease and latterly of scleroderma suggest that they were paraneoplastic
manifestations. It is now ten months since tumour resection and the
cutaneous scleroderma is gradually improving.
Scleroderma has been previously reported as a paraneoplastic
phenomenon coexisting most frequently with adenocarcinomas of lung, breast
and stomach [3,4]. These patients were three times more likely to be
female: all had cutaneous manifestations of scleroderma but less than half
had systemic features [4]. We found no previous reports of scleroderma in
association with pseudomyxoma peritonei although dermatomyositis has been
reported preceding the diagnosis of this tumour by six months [5].
These collected case reports highlight that occult malignancies can present with musculoskeletal symptoms and the clinician should always be vigilant for these paraneoplastic manifestations.
References
1. Denschlag D, Reiner E, Vaith P, Tempfer C, Keck C. Palmar
fasciitis and polyarthritis as a paraneoplastic syndrome associated with
tubal carcinoma: a case report. Ann Rheum Dis 2004; 63: 1177-1178.
2. von Lilienfeld-Toal M, Merkelbach-Bruse S, Dumoulin FL. An unusual
presentation of a common disease. Ann Rheum Dis;63:887-888.
4. Caldwell DS, McCallum RM. Rheumatological manifestations of Cancer. Med
Clin N Am 1986;70: 385-417.
5. Maekawa Y, Nakamura K, Nogami R. A Case of Dermatomyositis Associated
with Pseudomyxoma Peritonei Originating from Mucinous Adenocarcinoma of
the Appendix. J Dermatol 1992; 19: 420-3.
Over quarter of a century of experience with injecting steroids has
led me to believe in the value of steroid injections for OA of small and
large joints. I have used Depot-Medrone with lidocaine for the CMC
Joint, especially in the elderly who have disabling CMC joint OA, leading
to inability to lift a pot of Tea, an extremely important activity of
daily living for the elderly at least in UK!
Many...
Over quarter of a century of experience with injecting steroids has
led me to believe in the value of steroid injections for OA of small and
large joints. I have used Depot-Medrone with lidocaine for the CMC
Joint, especially in the elderly who have disabling CMC joint OA, leading
to inability to lift a pot of Tea, an extremely important activity of
daily living for the elderly at least in UK!
Many of these patients cannot tolerate many analgesics and anti
inflammatory drugs, compounded by co-morbidities. In my experience the
pain relief has been as long as 3 years, but could be as short as 4 weeks
for very few. The pain and functional improvement has been longest with
injections for OA in CMC Joints and first Metartarsophalageal joints
without large osteophytes. A community based study on a larger number of
patients will be illuminating! CMC Joint OA is very common in primary
care.
We read with interest the article by Kauppi, Barcelos and da Silva
which discussed the importance of the specific evauation of the cervical
spine in the patients with rheumatoid arthritis (RA) [1]. Magnetic
resonace imaging (MRI) is becoming surgical golden standard for the
confirmation of compressive cervical myelopathy but is expensive and time
consuming. Functional MRI is the most reliable exami...
We read with interest the article by Kauppi, Barcelos and da Silva
which discussed the importance of the specific evauation of the cervical
spine in the patients with rheumatoid arthritis (RA) [1]. Magnetic
resonace imaging (MRI) is becoming surgical golden standard for the
confirmation of compressive cervical myelopathy but is expensive and time
consuming. Functional MRI is the most reliable examination but almost
impossible to perform in majority of patients with atlantoaxial
instability and long lasting RA.
Forward atlantoaxial subluxation is the most frequent dislocation and easy
to detect on standard and dynamic radiograms of the cervical spine.
Steel's rule of third is plausible screening method for assessment of
sagittal spinal canal in C1 level (in sagittal diameter of atlas one third
of the space occupies dens, one third spinal cord and one third is free
space that allows secure movements in this region) [2]. Theoretically the
maximal and still safe atlantodental distance could be one third of the
atlas saggittal diameter [2, 3]. This is partial explanation for low
incidence of neural complications in patients with RA of craniovertebral
junction. The aim of clinical evaluation is to detect early signs of
neural involvement. Somatosensory evoked potentials (SSEPs) represent a
neuroelectrophysilogical method that estimate the function of the
posterior column of the spinal cord [4, 5, 6, 7, 8]. It allows early
detection of disorders of cervical neural pathways before the clinical
symptoms develop. SSEPs could be perforemed in neutral and dynamic fashion
what gives information is there any compressive moment in different
positions [5].
In our department we are following the next steps in the approach to the
patient with RA and cervical spine involvement: 1. radiological assessment
(standard and lateral flexion-extension views of cervical spine and open
mouth views of dens) of all patients with RA and cervicogenic symptoms
regardless of the duration of disease and all patients with RA lasting 5
years and more; 2. SSEPs for median nerve in standard and functional
position of patient' head when there is radiologically significant
atlantoaxial dislocaton (> 4mm or more in maximum flexion) or any
other changes related to RA activity; 3. MRI is last step depending of the
previous findings; 4. consideration of more agressive pharmacological
treatment, cervical orthosis or surgery.
Neuroradiological analyses visualise bone displacment and erosions,
proliferative rheumatoid tissue and compression of spinal cord but do not
express functional integrity of neural pathways. SSEPs is an accepted
method for evaluating sensory functions of the central nervous system with
the possibility to detect subclinical disorders. SSEPs should be
registered in neutral position, flexion and rotations of the cervical
spine.
We investigated 56 female hospital patients with RA who were
admitted to the Department of Rheumatology, University Hospital Rebro,
Zagreb, Croatia during one year [5]. Twenty five (44%) had forward
atlantoaxial subluxation ranging from 4 to 17 mm. A total of 12 patients
had pathological SSEPs latencies for median nerve and among them 11 had
neck symptoms, 6 had abnormal neurological findings and 6 had forward
atlantoaxial subluxation. The pathological SSEPs findings were provoked by
movements of the neck in 9 out of 12 patients.
In conclusion, we would like to add radiological analysis of cervical
spine according Steel's rule of third and SSEPs functional examination as
valuable diagnostic tool for evaluation of rheumatoid cervical spine.
SSEPs results help to identify patients with cervical cord dysfunction
before detectable clinical signs develops and thus contribute to the
therapeutic decision making.
Ð Babiæ-Nagliæ¹, B Æurkoviæ ¹
Department of Rheumatology
University Hospital Rebro
Zagreb
Croatia
Correspondence to:
Prof. Ðurða Babiæ-Nagliæ, MD
Kišpatiæeva 12
Zagreb 10000
Croatia
dnaglic@kbc-zagreb.hr
References
1. Kauppi MJ, Barcelos A, da Silva JAP. Cervical complications of
rheumatoid arthritis. Ann Rheum Dis 2005; 64: 355-358.
2. Steel HH. Anatomical and mechanical consideartions of the atlantoaxial
articulations. J Bone Surg 1968; 50: 1481-1482.
3. Babiæ-Nagliæ Ð, Potoèki K, Æurkoviæ B. Clinical and radiological
features of atlantoaxial joints in rheumatoid arthritis. Z Rheumatol 1999;
58: 196-200.
4. Giraud P, Mauguiere F. Somatosensory evoked potentials in rheumatoid
polyarthritis with radiologic involvement of the cervical spine.
Neurophysiol Clin 1997; 27: 33-50.
5. Babiæ-Nagliæ Ð, Nesek-Maðariæ V, Potoèki K, Lelas-Bahun N, Æurkoviæ B.
Early diagnosis of rheumatoid cervical myelopathy. Scand J Rheumatol 1997;
26: 247-52.
6. Tsiptsios I, Fotiou F, Sitzoglou K, Fountoulakis KN. Neurophysilogical
investigation of cervical spondylosis. Electromyogr Clin Neurophysiol
2001; 41: 305-13.
7. Hayashida T, Ogura T, Hase H, Osawa T, Hirasawa Y. Estimation of
cervical cord disfunction by somatosensoray evoked potentials. Muscle
Nerve 2000; 23: 1589-1593.
8. Dvorak J, Sutter M, Herdmann J. Cervical myelopathy: clinical and
neurophysiological evaluation. Eur Spine J 2003; 12 (suppl 2): S181-187.
We read with interest the analysis of pro- and anti-inflammatory cytokines in pregnant women with chronic inflammatory arthritis, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and ankylosing spondylitis, recently described by Oestensen et al [1].
Besides direct measurement of cytokine serum levels, they analysed the levels of soluble CD30 (sCD30), a surface protein...
We read with interest the analysis of pro- and anti-inflammatory cytokines in pregnant women with chronic inflammatory arthritis, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and ankylosing spondylitis, recently described by Oestensen et al [1].
Besides direct measurement of cytokine serum levels, they analysed the levels of soluble CD30 (sCD30), a surface protein released by CD30+ T cells which have been associated with the production of Th2-type anti-inflammatory cytokines (in particular IL-4 and, in part, IL-10) [2,3]. High levels of sCD30, that could represent, therefore, an indirect marker of counter-regulatory cell activity, have been described in several chronic inflammatory rheumatic disorders, including RA [3,4]. In their study, however, Oestensen et al. did not find any differences in sCD30 serum levels between RA and control non-pregnant women. Moreover, in contrast to the expected finding of increased sCD30 levels during pregnancy, that usually provides beneficial effect on RA disease activity, a progressive decrease of serum levels in the course of pregnancy was observed, although median of sCD30 from all sera of RA pregnant women demonstrated higher levels than those from non-pregnant RA and control subjects.
These apparently conflicting data may be explained by some observations. High serum levels of sCD30 in RA, particularly in patients with circulating rheumatoid factor, have been confirmed in different studies, but the sCD30 concentration reported is very wide [4-7]. Indeed, the median value we found in a large series of 148 RA patients was 79.7 U/ml, significantly different from the values of age- and sex-matched healthy controls (19.1 U/ml, p<_0.001 but="but" ranging="ranging" from="from" _9.5="_9.5" to="to" _515="_515" u="u" ml.="ml." p="p"/> Longitudinal evaluations performed in several of these patients usually showed steady levels over time in subjects with stable disease activity, but showed significant changes after starting remission-inducing treatments, such as anti-TNFa-blockade (unpublished data). It is important to note, however, that these changes are essentially observed in subjects with medium-high levels of sCD30, whereas low basal values remain persistently stable irrespective of disease activity.
In the Oestensen’s study, median of sCD30 values in non-pregnant women is rather low and this may be due to both low number and different selection of the patients, for example prevalent inclusion of patients with seronegative RA, mild disease or in remission. In addition, the pooling of samples from the three trimesters of pregnancy may be misleading and, in our opinion, the very low number of pre-pregnant women does not allow to draw any conclusion. Finally, the inclusion in RA group of patients with JIA may be not correct due to possible different roles exerted by CD30+ T cells in the JIC subgroups [6]. The persistently low levels of sCD30 in the longitudinal evaluation are in agreement with the observation of stable values of sCD30 when they are around the normal range and the slight decrease may be due in fact to enhancement of plasma volume due to pregnancy, as suggested by the Authors. This finding is in line with our analysis in two RA women followed-up before and during pregnancy, whose sCD30 values remained firmly below 25 U/ml also after delivery (Table 1). On the contrary, an increase of sCD30 values was observed during pregnancy in other 4 RA patients with basal sCD30 levels ranging from 60 to 348 U/ml. The increase was already observed in the first trimester and persisted until the delivery.
The lack of correlation of sCD30 circulating levels and disease activity scores in the Oestensen’ RA cohort is not surprising, since an inverse correlation between an inflammation marker, such as C-reactive protein, and sCD30 has been found only in patients with early disease and high sCD30 serum levels before starting disease modifying anti-rheumatic drugs. [8]
Although we are unable to explain the reasons of the absence of significant levels of sCD30 in a subset of RA patients, the high levels found in 4 of our 6 pregnant patients support the postulated counter-regulatory role of CD30+ T cells in RA. In addition, these findings point out the complex cytokine network characterizing RA synovitis, where spontaneous or physiological events, such as pregnancy, and/or treatment-induced prevalence of pro- or anti-inflammatory activity lead to disease flare or remission. [9] In this setting, we agree with Oestensen’s statement that simultaneous evaluation of markers not only of Th2-, but also of Th1-type cytokine-producing lymphocytes actively involved in RA synovitis, such as CD26+ cells,10,11 may help to better define the imbalance present in rheumatoid synovial microenvironment.
References
(1). Oestensen M, Foerger F, Nelson JL, et al. Pregnancy in patients with rheumatic diseases : Anti.inflammatory cytokines increase in pregnancy and decrease post-partum. Ann Rheum Dis Published Online First November 11, 2004. doi:10:1136/ard.2004.029538.
(2). Gerli R, Pitzalis C, Bistoni O, et al. CD30+ T cells in rheumatoid synovitis: mechanisms of recruitment and functional role. J Immunol 2000;164:4399-407.
(3). Gerli R, Lunardi C, Vinante F, et al. Role of CD30+ T cells in rheumatoid arthritis: a counter-regulatory paradigm for Th1-driven diseases. Trends Immunol 2001;22:72-7.
(4). Gerli R, Muscat C, Bistoni O, et al. High levels of the solubile form of CD30 molecule in rheumatoid arthritis (RA) are expression of CD30+ T cells involvement in the inflamed joints. Clin Exp Immunol 1995;102:547-50.
(5). Ichikawa Y, Yoshida M, Yamada C, et al. Circulating soluble CD30 levels in primary Sjögren’s syndrome, SLE and rheumatoid arthritis. Clin Exp Rheumatol 1998;16:759-60.
(6). de Kleer M, Kamphuis SM, Rijkers GT, et al. The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum 2003;48:2001-10.
(7). Okamoto A, Yamamura M, Iwahashi M, et al. Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis. Acta Med Okoyama 2003;57:267-77.
(8). Gerli R, Bistoni O, Lunardi C, et al. Solubile CD30 in early rheumatoid arthritis as a predictor of good response to second-line therapy. Rheumatology 1999;38:1282-4.
(9). Gerli R, Lunardi C, Pitzalis C. Unmasking the anti-inflammatory cytokine response in rheumatoid synovitis. Rheumatology 2002;41:1341-5.
(10). Muscat C, Bertotto A, Agea E, et al. Expression and functional role of 1F7 (CD26) antigen on peripheral blood and synovial fluid T cells in rheumatoid arthritis patients. Clin Exp Immunol 1994;98:252-6.
(11). Gerli R, Muscat C, Bertotto A, et al. CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis. Clin Immunol Immunopathol 1996;80:31-7.
Table 1: Serum levels of sCD30 (U/ml) in
6 RA patients before, during and after pregnancy
With the increasing number of patients now being treated with tumour
necrosis factor alpha (TNF-alpha) blocking agents, the publication of an
updated consensus statement in the Advances in Targeted Therapies VI
supplement of Annals of the Rheumatic Diseases was both timely and
relevant. However we notice that conflicting advice on the management of
patients with Hepatitis B Virus (HBV) infection is...
With the increasing number of patients now being treated with tumour
necrosis factor alpha (TNF-alpha) blocking agents, the publication of an
updated consensus statement in the Advances in Targeted Therapies VI
supplement of Annals of the Rheumatic Diseases was both timely and
relevant. However we notice that conflicting advice on the management of
patients with Hepatitis B Virus (HBV) infection is given in this
supplement in 2 separate articles. Furst et al[1] comment on the paucity of
data on this situation which leads them to conclude that "TNF blockers
should not be used in patients with HBV infection (category C evidence)".
In a subsequent article, Calabrese et al[2] review the evidence obtained
from 4 cases and conclude that when there is no alternative to TNF
blockade the potential exists for safe administration of TNF blocking
agents through careful monitoring of viral status, prior or concurrent
prescription of lamuvidine and/or temporary discontinuation of anti-TNF
therapy should HBV re-activation occur. Given that HBV infection and
inflammatory arthritis are common conditions, this is a not uncommon
situation that most rheumatology centres will encounter at some point and
we wish to clarify the correct position on the management of patients with
HBV infection and TNF-alpha blocking agents.
Since Calabrese et al’s[2] article, Esteve et al[3] have reported 3 cases
of Crohn’s disease patients with chronic HBV who received infliximab. From
80 patients tested prospectively for HBV prior to infliximab therapy for
Crohn’s disease, 3 were identified with chronic HBV infection and 2 of the
3 patients developed severe reactivation of HBV at 2 and 3 months after
the last infliximab infusion. One patient made a complete recovery after 3
months while the second died from advanced hepatic failure. A third
patient was treated with lamivudine therapy prior to treatment with
infliximab therapy and has had no clinical or biochemical worsening of
liver disease either during or after therapy.
We also have experience of safely and successfully using TNF blockade
in 2 patients with RA and chronic HBV infection who had failed standard
DMARD therapy and continued to have severely active RA. A 50 year old
woman with RA and chronic HBV infection who had failed treatment with 5
DMARDs – including cyclophosphamide – was commenced on etanercept 25mg
twice weekly s.c. At present she has completed 12 months of treatment with
a reduction in DAS28 from 7.22 to 5.56. She did not receive any antiviral
therapy prior to or during etanercept treatment and has had no evidence of
HBV reactivation - HBV surface antigen is negative and HBV DNA
undetectable. Etanercept was recently stopped due to persistent diarrhoea
and she continues on treatment with adalimumab which has been temporarily
discontinued during surgery for atlanto-axial subluxation. In a second
case, a 62 year old woman with RA and chronic HBV infection (HBsAg
negative) who had failed treatment with 3 DMARDs received etanercept 25mg
twice weekly in combination with 15mg methotrexate s.c. After 3 months
DAS28 reduced from 8.16 to 2.63. No antiviral therapy was given prior to
treatment with etanercept, and we have seen no evidence of HBV
reactivation to date – HBV DNA undetectable. She has now had 6 months of
treatment with etanercept with no complications.
Clearly the limited number of reports of anti-TNF therapy in HBV
infected patients raise a number of important issues. We believe that the
currently available data suggests that TNF blockade is a therapeutic
option in patients with RA and chronic HBV infection, though the
risk/benefit ratio must be carefully assessed in each patient.
Furthermore, the European Association for the Study of the Liver
International Consensus on Hepatitis B has produced guidelines on the safe
treatment of patients with HBV who require immunosuppressive treatment.
These guidelines led Calabrese et al[2] to advise that TNF blockade may be
prescribed in patients with HBV infection. This should include assessment
by a hepatologist and close monitoring of liver enzymes and HBV viral load
during TNF blockade. Anti-viral therapy is effective for HBV re-activation
but it is not yet clear whether anti-viral therapy should be administered
prior to or during anti-TNF therapy or solely when HBV re-activation is
detected. We believe that since HBV screening has not been mandatory in
the pre-treatment assessment of patients receiving TNF blockade there are
likely to already be a small but considerable number of patients with HBV
infection who are already receiving TNF blockade. Further reporting of
these cases would help clarify the risks of HBV re-activation, whether it
is more frequent with infliximab, etanercept, or adalimumab and provide
information on the outcome of anti-viral treatment.
Graham Raftery 1, Bridget Griffiths 2, Lesley Kay 3, David Kane 4.
Freeman Hospital, High Heaton, Newcastle upon Tyne, NE7 7DN, UK.
Correspondence to: Dr. Graham Raftery, Department of Rheumatology,
Freeman Hospital, High Heaton, Newcastle-upon-Tyne, NE7 7DN, UK.
1 Furst D E, Breedveld F C, Kalden J R, Smolen JS, Burmester G R,
Bijlsma, J W, et al. Updated consensus statement on biologic agents,
specifically tumour necrosis factor alpha; (TNFalpha) blocking agents and
interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic
diseases, 2004. Ann Rheum Dis 2004;64(Suppl 2):ii2-ii12.
2 Calabrese L H, Zein N, Vassilopoulos. Safety of antitumour necrosis
factor (anti-TNF) therapy in patients with chronic viral infections:
hepatitis C, hepatitis B and HIV infection. Ann Rheum Dis 2004;63(Suppl
2)ii18-ii24.
3 Esteve M, Saro C, Gonzalea-Huix, Suarez F, Forne M, Viver JM.
Chronic hepatitis B reactivation following infliximab therapy for Crohn’s
disease patients: need for primary prophylaxis. Gut 2004 Sep;53(9):1363-5.
We read with interest the observational, retrospective study by
Fautrel and colleagues on the efficacy of anti-TNFĄ agents (aTNF) in
refractory adult onset Still¡¦s disease (AOSD) [1].
The authors conclude
that aTNF is not as effective in AOSD as in rheumatoid arthritis (RA) or
the spondyloarthrotopathies and may be helpful only in some AOSD cases.
This conclusion cannot be fully supporte...
We read with interest the observational, retrospective study by
Fautrel and colleagues on the efficacy of anti-TNFĄ agents (aTNF) in
refractory adult onset Still¡¦s disease (AOSD) [1].
The authors conclude
that aTNF is not as effective in AOSD as in rheumatoid arthritis (RA) or
the spondyloarthrotopathies and may be helpful only in some AOSD cases.
This conclusion cannot be fully supported by the results presented and we
would like to suggest an alternative interpretation.
Firstly, it is
difficult to draw parallels between AOSD and RA studies, due to
differences in the nature of these conditions, severity of disease on
inclusion, response criteria used, and overall study designs. If
anything, complete remission with aTNF appears commoner in this study of
AOSD than in multiple RA trials. Secondly, besides the retrospective
design, there are other limitations that would also suggest that any
conclusions should be viewed with caution. These include the significant
heterogeneity of concomitant treatment, the exclusively clinician-based,
subjective, assessment of response, possible slight overrepresentation of
females and inclusion of 3 patients that may have had juvenile Still¡¦s
disease [2] rather than AOSD.
More importantly, there may be a differential response to the two
aTNF agents used. Excluding patients with juvenile Still¡¦s disease,
Etanercept was used as the first agent in 9 AOSD patients: 2 failed to
respond, 6 achieved partial remission, and 1 achieved complete remission
(with concomitant prednizolone 80 mg/day!). In contrast, in the 9 AOSD
patients who received infliximab as the first agent, there were 5 partial
remissions, 4 complete remissions and no failures (chi-squared test for
trend=3.846, P=0.0499). Infliximab was given in one additional AOSD
patient after failure of Etanercept and resulted in partial response,
while 2 other patients had also Infliximab-induced partial responses after
a similar Etanercept-induced response. It is interesting that the only 3
patients who failed to respond to Infliximab are those who could be
classified as juvenile Still¡¦s disease.
Differential efficacy of aTNF agents is well-described in Crohn¡¦s
disease [3], may also occur in Adamantiades-Behcet¡¦s disease [4, 5]
and, we suggest, AOSD. Allowing for reporting bias, all of the AOSD cases
reported thus far appear to have had benefit from Infliximab [1, 6-10],
even cases refractory to pulse steroid therapy. We suggest that, on
current evidence, Infliximab is a very reasonable treatment choice in
refractory AOSD. The possibility of a differential response between
Infliximab and Etanercept in AOSD requires further investigation.
References
(1). Fautrel B, Sibilia J, Mariette X, Combe B. Tumour necrosis factor
(alpha) blocking agents in refractory adult Still¡¦s disease: an
observational study of 20 cases. Ann Rheum Dis 2005; 64:262-6
(2). Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y,
Kashiwagi H et al. J Rheumatol 1992; 19: 424-30
(3). van Deventer SJH. Transmembrane TNF-alpha, induction of apoptosis,
and the efficacy of TNF-targeting therapies in Crohn's disease.
Gastroenterology 2001; 121:1242-6
(4). Sfikakis PP. Behcet's disease: a new target for anti-tumour
necrosis factor treatment. Ann Rheum Dis 2002; 61(suppl 2):ii51-3
(5). Sfikakis PP, Kaklamanis PH, Elezoglou A, Katsilambros N,
Theodossiadis PG, Papaefthimiou S, et al. Infliximab for recurrent, sight-
threatening ocular inflammation in Adamantiades-Behcet disease. Ann
Intern Med 2004; 140: 404-6
(6). Cavagna L, Caporali R, Epis O, Bobbio-Pallavicini F, Montecucco C.
Infliximab in the treatment of adult Still's disease refractory to
conventional therapy. Clin Exp Rheum 2001; 19: 329-32
(7). Caramaschi P, Biasi D, Carletto A, Bambara LM. A case of adult
onset Still's disease treated with infliximab. Clin Exp Rheumatol 2002;
20: 113
(8). Dechant C, Schauenberg P, Antoni CE, Kraetsch HG, Kalden JR,
Manger B. Longterm outcome of TNF blockade in adult-onset Still's disease.
Dtsch Med Wochenschr 2004; 129: 1308-12
(9). Bonilla Hernan MG, Cobo Ibanez T, de Miguel Mendieta E, Martin-
Mola E. Infliximab (anti-TNF alpha) treatment in patients with adult
Still¡¦s disease. Experience in 2 cases. An Med Interna 2004; 21: 23-6
(10). Kokkinos A, Iliopoulos A, Greka P, Efthymiou A, Katsilambros N,
Sfikakis PP. Successful treatment of refractory adult-onset Still's
disease with infliximab. A prospective, non-comparative series of four
patients. Clin Rheumatol 2004; 23: 45-9.
Lee and Kavanagh [1] report on the need for greater reporting of
socio-economic status and race in clinical trials.
This raises the wider issue of encouraging patients from ethnic
minorities to participate in clinical trials in the first place.
There are several known barriers to the involvement of ethnic
minorities in clinical trials. Race often co-locates with low socio-
economic status, literacy levels and educational attainment. These
factors compound related factors such as distrust of physicians and
clinical studies, insufficient knowledge about trials and low expectations
from clinical trials.
Whilst it is neither essential nor appropriate that ethnic minority
patients are included in all clinical trials, their inclusion is
particularly relevant in order to test hypotheses about possible ethnic
differences, for example how patients respond to drugs, how they
metabolise drugs, impact of concurrent diseases as well as side effects of
drugs.
Where appropriately done, ethnic minority inclusion in clinical
research is potentially very rewarding and offsets the increase costs such
as the cost of providing translators.
Reference
(1). Lee SJ & Kavanaugh A. A need for greater reporting of socio-
economic status and race in clinical trials. Ann Rheum Dis Dec 2004; 63:
1700-1701
Fautrel et al [1] recently reported the cases of 20 adults with Still's
disease who were treated with TNF alpha blocking agents. Most patients
only achieved partial remission and there were only 2 cases of sustained
remission of more than one year, which contrasts with the much higher
response rates observed in patients with rheumatoid arthritis.
Fautrel et al [1] recently reported the cases of 20 adults with Still's
disease who were treated with TNF alpha blocking agents. Most patients
only achieved partial remission and there were only 2 cases of sustained
remission of more than one year, which contrasts with the much higher
response rates observed in patients with rheumatoid arthritis.
In this paper, the authors never refer to the pediatric experience.
However, they indicate that the disease had a childhood onset in 4 of
their patients and they insist on the scantiness of available data in
adults. Although the disease is also rare in children, several studies had
been published reporting the experience of etanercept treatment in more
than one hundred patients with systemic-onset juvenile rheumatoid
arthritis (JRA)/juvenile idiopathic arthritis (JIA), i.e. childhood-onset
Still's disease. [2-5] Moreover, we and others showed that these patients
were significantly less responsive to anti-TNF alpha therapy than patients
with other forms of JIA. [4-5]
When dealing with the treatment of rare diseases, pediatricians and
rheumatologists have to consider each others' experience.
References
(1). Fautrel B, Sibilia J, Mariette X, Combe B. Tumour necrosis factor a
blocking agents in refractory adult Still's disease: an observational
study of 20 cases. Ann Rheum Dis. 2005;64:262-266.
(2). Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton
JJ, et al. Etanercept in children with polyarticular juvenile rheumatoid
arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med.
2000;342:763-9.
(3). Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC,
et al. Long-term efficacy and safety of etanercept in children with
polyarticular-course juvenile rheumatoid arthritis: interim results from
an ongoing multicenter, open-label, extended-treatment trial. Arthritis
Rheum. 2003;48:218-26.
(4). Quartier P, Taupin P, Bourdeaut F, Lemelle I, Pillet P, Bost M, et
al. Efficacy of etanercept for the treatment of juvenile idiopathic
arthritis according to the onset type. Arthritis Rheum. 2003;48:1093-101.
(5). Horneff G, Schmeling H, Biedermann T, Foeldvari I, Ganser G,
Girschick HJ, et al. The German etanercept registry for treatment of
juvenile idiopathic arthritis. Ann Rheum Dis. 2004;63:1638-44.
We read with interest the study by Cainelli et al [1] on the presence
of antinuclear antibodies (ANA) in normal healthy individuals from an
infectious environment. They point out that the presence of ANA may not be
predictive of Systemic Lupus Erythematosus in individuals from tropical
regions.
These observations confirm previous such studies from West Africa. We
would point out howev...
We read with interest the study by Cainelli et al [1] on the presence
of antinuclear antibodies (ANA) in normal healthy individuals from an
infectious environment. They point out that the presence of ANA may not be
predictive of Systemic Lupus Erythematosus in individuals from tropical
regions.
These observations confirm previous such studies from West Africa. We
would point out however that these findings are not confined to
antinuclear antibodies. Several other antibodies including rheumatoid
factors, antithyroglobulin antibodies, antiDNA antibodies and
anticardiolipin antibodies have been found in individuals with various
tropical acute and chronic infections such as, malaria, tuberculosis,
leprosy, schistosomiasis and filariasis as well as in healthy individuals
in these environments. [2,3]
As Cainelli et al point out; the reason for these autoantibodies in
disease and health in individuals from the tropics is still largely
unknown but potential explanations include molecular mimicry or polyclonal
B cell activation.
As a result of these observations, we would recommend caution in the
interpretation of these autoantibody tests in persons from the tropics.
References
(1). Cainelli F, Betterle C, & Vento S. Antinuclear antibodies are
common in an infectious environment but do not predict systemic lupus
erythematosus. Ann. Rheum. Dis, Dec 2004; 63: 1707 – 1708
(2). Greenwood BM, Muller AS & Valkenburg HA (1971) Rheumatoid
factor in Nigerian sera. Clinical and experimental immunology 9: 161-173.
(3). Adebajo AO, Charles P, Maini RN, HazlemanBL (1993). Autoantibodies
in malaria, tuberculosis and hepatitis B in a West African population.
Clin. Exp. Immunol. 92:73-6
Tubach and colleagues [1] propose an 8-item shortened version of the
WOMAC physical function subscale which they consider promising for
clinical use and large scale surveys and clinical trials.
The authors report that the shortened measure’s test retest
reliability
and responsiveness are similar to those of the complete physical
function subscale; the internal consistency of the shortened...
Tubach and colleagues [1] propose an 8-item shortened version of the
WOMAC physical function subscale which they consider promising for
clinical use and large scale surveys and clinical trials.
The authors report that the shortened measure’s test retest
reliability
and responsiveness are similar to those of the complete physical
function subscale; the internal consistency of the shortened measure
(0.84) is less than that of the full length measure (0.93). I have several questions concerning the methods:
1. Was the entire WOMAC, including
pain and stiffness subscales, administered?
2. Were responses to the
shortened version abstracted from the lengthened version?
3. If the
answer to the previous question is “yes,” was the difference in sample
size for the responsiveness analysis (shortened version n=1169; full
length n=1048) a result of missing item values?
4. Would it be possible
to provide descriptive statistics (mean, standard deviation) for the
shortened version?
5. Could the authors present the standard error of
measurement associated with the internal consistency estimates?
The
answer to the last question would be helpful in labeling the
measurement error at an instant in time and in ascertaining the
consequence of using the shortened version to make confident—in a
reliability sense—decisions concerning an individual patient’s functional
status at an instant in time.
Although the WOMAC has been the principal self-report functional
status
measure for patients with osteoarthritis of the hip or knee for 2-
decades, there is consistent evidence in the literature refuting the
measure’s factorial validity [2-5] The WOMAC purports three subscales—
pain, stiffness, physical function—yet the pain and function subscales
have been repeatedly shown to overlap [2-5]. That pain and function are
not completely distinct is to be expected; however, the OMERACT III
group deemed them distinct enough to warrant independent
assessment [6]. At issue is the extent to which the overlap in responses to
the pain and function subscales is real or biased due to a common item
phrasing in pain and function items [4]. It would be informative to know
whether the proposed shortened function scale represented a factor
distinct from pain in the study sample.
As a matter of interest I ran a factor analysis on the pain and
shortened
function scale proposed by the authors on a sample of 310 patients with
osteoarthritis of the hip or knee reported previously in the peer reviewed
literature [4]. I ran two analyses with oblique rotation, one used the
eigenvalue greater than 1 rule and the other restricted the analysis to
two factors. The eigenvalue greater than 1 rule identified three factors.
Neither analysis grouped the items by purported subscales of pain and
function.
The consequence of poor factorial validity is that one may not be
assessing what she/he is believed to be assessing. To examine the
consequence of the apparently poor factorial validity of the proposed
shortened version of the WOMAC function scale, I examined the
measure’s ability to detect deterioration in a group of patients
undergoing total hip or knee arthroplasty. This sample is described in a
previous paper [7]. The rationale being that physical function deteriorates
between preoperative and postoperative assessment performed within
16 days of surgery. I repeated the analysis reported previously in a peer-
reviewed paper [7] (n=104) and found the following for the proposed
shortened physical function subscale: mean pre-operation 15.7
(sd=5.2); mean post-operation (median assessment interval was 8 days,
1st, 3rd quartiles were 7, 10 days) 15.9 (sd=5.6); and the standardized
response mean was –0.02 (95% CL: -0.23, 0.17). That the confidence
interval for the standardized response mean includes the value zero
indicates the measure was not able to detect deterioration in this group.
Tubach and colleagues acknowledge that further evaluation of their
shortened version is required. I believe an important next step is to
ascertain whether the measure possesses factorial validity.
References
(1). Tubach F, Baron G, Logeart I, Dougados M, Bellamy N, Ravaud P.
Using patients' and rheumatologists' opinions to specify a short form of
the WOMAC function subscale. Ann Rheum Dis 2005;64:75-79.
(2). Faucher M, Poiraudeau S, Lefevre-Colau MM, Rannou F, Fermanian
J, Revel M. Algo-functional assessment of knee osteoarthritis:
comparison of the test-retest reliability and construct validity of the
WOMAC and Lequesne indexes. Osteoarthritis Cartilage 2002;10:602
-10.
(3). Thumboo J, Chew LH, Soh CH. Validation of the Western Ontario
and Mcmaster University osteoarthritis index in Asians with osteoarthritis
in Singapore. Osteoarthritis Cartilage 2001;9:440-6.
(4). Stratford PW, Kennedy DM. Does parallel item content on WOMAC's
Pain and Function Subscales limits its ability to detect change in
functional status? BMC Musculoskelet Disord 2004;5:17.
(5). Guermazi M, Poiraudeau S, Yahia M, Mezganni M, Fermanian J,
Habib Elleuch M, et al. Translation, adaptation and validation of the
Western Ontario and McMaster Universities osteoarthritis index (WOMAC)
for an Arab population: the Sfax modified WOMAC. Osteoarthritis
Cartilage 2004;12:459-68.
(6). Bellamy N, Kirwan J, Boers M, Brooks P, Strand V, Tugwell P, et al.
Recommendations for a core set of outcome measures for future phase
III clinical trials in knee, hip, and hand osteoarthritis. Consensus
development at OMERACT III. J Rheumatol 1997;24:799-802.
(7). Stratford PW, Kennedy DM, Hanna SE. Condition-specific Western
Ontario McMaster Osteoarthritis Index was not superior to region-
specific Lower Extremity Functional Scale at detecting change. J Clin
Epidemiol 2004;57:1025-1032.
Dear Editor,
We read with interest the case report by Denschlag et al. [1]. In addition, von Lilienfield-Toal et al. also recently described the presentation of adult onset Still’s disease associated with occult breast malignancy [2]. These case reports remind us that rheumatic symptoms may precede the diagnosis of an underlying neoplasm. We recently observed an atypical presentation of scleroderma associated wit...
Dear Editor,
Over quarter of a century of experience with injecting steroids has led me to believe in the value of steroid injections for OA of small and large joints. I have used Depot-Medrone with lidocaine for the CMC Joint, especially in the elderly who have disabling CMC joint OA, leading to inability to lift a pot of Tea, an extremely important activity of daily living for the elderly at least in UK! Many...
Dear Editor,
We read with interest the article by Kauppi, Barcelos and da Silva which discussed the importance of the specific evauation of the cervical spine in the patients with rheumatoid arthritis (RA) [1]. Magnetic resonace imaging (MRI) is becoming surgical golden standard for the confirmation of compressive cervical myelopathy but is expensive and time consuming. Functional MRI is the most reliable exami...
Dear Editor,
We read with interest the analysis of pro- and anti-inflammatory cytokines in pregnant women with chronic inflammatory arthritis, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and ankylosing spondylitis, recently described by Oestensen et al [1].
Besides direct measurement of cytokine serum levels, they analysed the levels of soluble CD30 (sCD30), a surface protein...
Dear Editor,
With the increasing number of patients now being treated with tumour necrosis factor alpha (TNF-alpha) blocking agents, the publication of an updated consensus statement in the Advances in Targeted Therapies VI supplement of Annals of the Rheumatic Diseases was both timely and relevant. However we notice that conflicting advice on the management of patients with Hepatitis B Virus (HBV) infection is...
Dear Editor,
We read with interest the observational, retrospective study by Fautrel and colleagues on the efficacy of anti-TNFƒÑ agents (aTNF) in refractory adult onset Still¡¦s disease (AOSD) [1].
The authors conclude that aTNF is not as effective in AOSD as in rheumatoid arthritis (RA) or the spondyloarthrotopathies and may be helpful only in some AOSD cases. This conclusion cannot be fully supporte...
Dear Editor,
Lee and Kavanagh [1] report on the need for greater reporting of socio-economic status and race in clinical trials.
This raises the wider issue of encouraging patients from ethnic minorities to participate in clinical trials in the first place.
There are several known barriers to the involvement of ethnic minorities in clinical trials. Race often co-locates with low socio- econo...
Dear Editor,
Fautrel et al [1] recently reported the cases of 20 adults with Still's disease who were treated with TNF alpha blocking agents. Most patients only achieved partial remission and there were only 2 cases of sustained remission of more than one year, which contrasts with the much higher response rates observed in patients with rheumatoid arthritis.
In this paper, the authors never refer...
Dear Editor,
We read with interest the study by Cainelli et al [1] on the presence of antinuclear antibodies (ANA) in normal healthy individuals from an infectious environment. They point out that the presence of ANA may not be predictive of Systemic Lupus Erythematosus in individuals from tropical regions.
These observations confirm previous such studies from West Africa. We would point out howev...
Dear Editor,
Tubach and colleagues [1] propose an 8-item shortened version of the WOMAC physical function subscale which they consider promising for clinical use and large scale surveys and clinical trials.
The authors report that the shortened measure’s test retest reliability and responsiveness are similar to those of the complete physical function subscale; the internal consistency of the shortened...
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