Rheumatology-47.10.letters 1587.159

2 Chakravarty K, McDonald H, Pullar T et al. BSR/BHPR guideline for disease- phosphokinase and immunoglobulin levels were normal. Liver modifying anti-rheumatic drug (DMARD) therapy in consultation with the British function tests were abnormal: aspartate transaminase 219 IU/l Association of Dermatologists. Rheumatology 2008;47:924–5.
3 University Hospital Birmingham NHS Foundation Trust. A–Z services: rheumatology.
(0–31), alanine transaminase 117 IU/l (0–31), GT 331 IU/l (2–30), Guidelines for the management of rheumatology patients. alkaline phosphatase 177 IU/l (30–130), bilirubin 6 mol/l (0–17) uk/Services/Rheumatology/Information%20for%20Clinicians/Guidelines.aspx and albumin 27 g/l (33–47). Hepatitis B surface antigen, hepatitis C antibody, HIV serology were negative and viral studies for CMV,Epstein–Barr virus, Herpes simplex virus and parvovirus did not indicate acute infection. ANAs (1 : 320), anti-Ro antibodies (>100 u/ml, normal range 0–20) and anti-thyroid microsomal anti- bodies were positive. Anti-double-stranded DNA, aCLs, ANCAs, Complement C1q and C8 deficiency in an individual anti-mitochondrial and anti-liver/kidney microsomal antibodieswere negative. Percutaneous liver core biopsy showed mild mono- with recurrent bacterial meningitis and adult-onset nuclear cell infiltrate in the portal tracts, moderate interface systemic lupus erythematosus-like illness hepatitis and focal necrosis and hepatocyte apoptosis withinparenchymal areas, features consistent with autoimmune hepatitis.
SIR, A 49-yr-old nulliparous Caucasoid lady presented with a Whilst C3 and C4 levels were normal, total complement several week history of florid oral ulceration, malaise, weight lossand fever. There was no rash, photosensitivity, arthralgia, alo- haemolytic activity (CH50) was repeatedly absent indicating poecia, RP, headache, ocular disturbance or recent foreign travel.
possible complement deficiency state. Reconstitution assays were Past medical history included hypothyroidism associated with performed in which sera with selective defects of complement anti-thyroid microsomal antibodies for which she was taking components or subunits were mixed with the patient sera and the thyroxine, bacterial meningitis at the age of 21 and 27 yrs and haemolytic activity of the resultant mixture measured (Table 1).
group A meningococcal septicaemia at the age of 44 yrs. There Serum deficient in either the C8 subunit of the C8 protein or the was a family history of consanguinity. She was dehydrated classical pathway component C1q did not restore haemolytic with low-grade pyrexia of 37.68C and had multiple oral aphthous activity to the patient’s sera. Normal CH50 was only restored ulcers. ESR was >100 mm/h, CRP 11 mg/l (0–10), Hb 9.4 g/l, following the addition of both C8 and C1q to the patient’s sera.
mean cell volume 92.1 fl, white cell count 5 Â 109/l, lymphocytes Antigenic assays confirmed complete absence of both C8 and 1 Â 109/l, platelet count 248 Â 109/l. Renal function, creatinine C1q in our patient (Table 1). The genetic basis of the C8 Classical pathway haemolytic assays:
Lysis when patient sera added to:
Sera depleted in classical pathway components: Sera depleted in terminal pathway components: Alternative pathway haemolytic assays:
Lysis when patient sera added to:
Complement C8 analysis:
Patient sera
Pooled human sera
C8b-deficient sera
Genetic basis of C8β deficiency = homozygous R427 Term in exon 9 of C8β gene Complement C1q analysis:
Patient sera
Pooled human sera
Genetic basis of C1q gene deficiency = homozygous G34R in C1qC genec aThe concentration of C8 and C1q added to 2 l of patient serum in 200 l diluent was 500 ng; bLMW C1q : lowmolecular weight C1q detected by sucrose gradient ultracentrifugation [3]; cConfirmed using Sfcl RFLP assay [7]. Aminoacid numbering refers to the translational start site (methionine is one), G: glycine; R: arginine; Term: stop codon.
deficiency was a homozygous null mutation within exon 9 of the 1 Kaufmann T, Hansch G, Rittner C et al. Genetic basis of human complement C8 beta C8B gene (R427Term, Table 1), a mutation previously identified deficiency. J Immunol 1993;150:4943–7.
2 Petry F. Molecular basis of hereditary C1q deficiency. Immunobiology 1998; as the commonest cause of C8 deficiency in Caucasoid individuals [1]. The C1q deficiency was due to a homozygous 3 Kirschfink M, Petry F, Khirwadkar K et al. Complete functional C1q deficiency point mutation (G34R) in the first coding exon of the C1qC gene, a mutation previously identified as a cause of C1q deficiency in 4 Pickering MC, Botto M, Taylor PR et al. Systemic lupus erythematosus, complement German, Indian and Saudi Arabian families [2]. The G34R deficiency, and apoptosis. Adv Immunol 2000;76:227–324.
mutation is associated with the presence of an abnormal, non- 5 Tedesco F, Densen P, Villa MA et al. Two types of dysfunctional eighth component functional C1q protein in circulation (low molecular weight C1q) of complement (C8) molecules in C8 deficiency in man. Reconstitution of normalC8 from the mixture of two abnormal C8 molecules. J Clin Invest 1983;71:183–91.
[3] which was detected in our patient (Table 1). Parental DNA was 6 Morgan BP, Walport MJ. Complement deficiency and disease. Immunol Today not available and no C1q or C8B mutations were present in a 7 Slingsby JH, Norsworthy P, Pearce G et al. Homozygous hereditary C1q deficiency A diagnosis of SLE-like illness associated with homozygous and systemic lupus erythematosus. A new family and the molecular basis of C1qdeficiency in three families. Arthritis Rheum 1996;39:663–70.
C1q deficiency was established together with homozygous 8 Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus.
C8 deficiency associated with recurrent bacterial meningitis.
Immunosuppressive therapy with prednisolone and AZA resultedin complete resolution of her transaminitis. AZA therapy was poorly tolerated, hence maintenance treatment with mycopheno- late mofetil was started. Three years later she remains in remission Advance Access publication 18 August 2008 and has not suffered any infective complications.
Homozygous C1q deficiency is a strong susceptibility factor for Comment on: Infliximab, etanercept and adalimumab for the development of an SLE-like illness: $93% of C1q-deficient the treatment of ankylosing spondylitis: cost-effectiveness individuals developed an SLE-like illness, typically beginning in childhood and frequently associated with cutaneous vasculitis,glomerulonephritis and cerebritis [4]. Homozygous deficiency of SIR, The recent editorial by Wailoo et al. [1] on cost-effectiveness complement C8 presents with selective deficiency of either C8 or evidence of TNF-inhibitors in AS is incorrect and worrying in C8- subunits [5] and is associated with an increased risk of recurrent neisserial infections, a feature common to all terminal First, the critique of the paper by Kobelt et al. [2] is factually pathway component deficiencies [6]. To our knowledge, this indi- wrong. The numbers cited by Wailoo and colleagues are nowhere to vidual represents the first reported case of combined C1q and C8 be found in this publication, and the ‘mistake’ is thus a deficiency. It was particularly striking that the onset of the SLE- construction. The point they make about the flawed review like illness was considerably later than that reported in individuals process, and the implicit critique of the reviewers and editors of lacking C1q alone (median onset 6 yrs) [4]. Moreover, her SLE- International Journal of Technology Assessment in Health Care is like illness appeared to be less severe: vasculitis, glomerulone- not substantiated. Instead, there is reason to ask how this editorial phritis or cerebritis have been described in C1q-deficient cleared this journal’s review process.
individuals with the G34R mutation [3, 7, 8]. Thus, we speculated Second, the authors seem to mix up information that they have that the inability to develop terminal pathway-mediated tissue gathered through participation in the NICE review process from injury (by virtue of the C8 deficiency) could have limited the a manufacturer submission, and what is actually published as a extent of SLE-induced organ damage in this individual. The scientific paper. We have no arguments with the procedure that scarcity of reports of SLE in individuals with terminal pathway NICE uses qualified reviewers to scrutinize the models and deficiency precluded any attempt to determine if the illness data supplied by the sponsors of the technologies assessed. But the severity in such cases differed from that seen in complement- privileged access to information these researchers have should sufficient SLE patients. However, this unique case supports an not be used to unfairly criticize and discredit other researchers.
important role for the membrane attack complex in the It happens now very often that the researchers involved in the development of tissue injury in SLE.
NICE process publish their finding as separate scientificpapers. This contributes to confusions about what is a NICEapplication and review, and what is a scientific paper. There aregood reasons to keep these two separated, particularly since reviewers can see all models submitted to NICE, but outside  Co-existing complement C8 deficiency ameliorated the SLE researchers have no access to the details of NICE models. This is even more important when the NICE evaluation process has notbeen completed.
In this case, the manufacturer of infliximab submitted an Disclosure statement: The authors have declared no conflicts of economic model to NICE and the Assessment Group (AG), along with the necessary raw data (in confidence) to replicate themodel. Within this process, the AG found a programmingerror. The submission stated that patients withdrawing from treatment return to baseline and then progress according to ICKERING , P. MACOR , J. FISH , P. DURIGUTTO , F. BOSSI , natural history, but the progression was inaccurately programmed in this particular arm of the model. The mistake was corrected 1Molecular Genetics and Rheumatology Section, Imperial College, and a new version submitted. The authors of the editorial London, UK, 2Department of Physiology and Pathology, University entered this process at a later stage as members of the of Trieste, Trieste, Italy and 3Institute of Medical Microbiology and Decision Support Unit (DSU) commissioned to evaluate the Hygiene, Johannes Gutenberg-University, Mainz, Germany assessment process, and thus use confidential information in an Correspondence to: M. C. Pickering, Molecular Genetics and Third, the editorial rises issues relating to what could be Rheumatology Section, Imperial College, London, UK.
considered conflict of interest and the motivations for the editorial. We understand that the unit at Sheffield University,

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