British Journal of Rheumatology 1991;30:476-479
LETTERS TO THE EDITOR pulmonary osteoarthropathic distribution of technetium-99m methylene diphosphonate in a case of Pneumocystis carinii pneumonia. J Nucl Med 1989;30:1563-7. Role of Prolactin in Autoimmune Diseases and Autoimmunity SIR—We have read with interest the excellent review about hypothalamic-pituitary mediated modulation of immune function: prolactin as a neuroimmune peptide, written by Chikanza and Panayi [1]. Although one of our articles presented in an American Rheumatism Association Congress in 1988 was cited in this review, the first published article that associates prolactin with autoimmune diseases (SLE) appeared in 1987 [2]. This article prompted an editorial written by Talal and Ahmed [3] that emphasized the importance of prolactin as an immunomodulator peptide. In 1990, Folomeev et al. [4] were able to confirm our results of hyperprolactinaemia in male patients with SLE. More recently, our group published an article about prolactin and gonadal hormones during pregnancy in SLE [5]. Higher serum prolactin levels were found in pregnant patients with SLE than those found in pregnant patients with RA or otherwise healthy pregnant controls. In April 1991, a review of prolactin, immunoregulation, and autoimmune diseases appeared in Seminars in Arthritis and Rheumatism [6]. This review was written by the Division of Rheumatology and Endocrinology of the University of South Florida and also by our group; it was based on our previous findings and included a review of the literature. The study done by Panayi etal. [7] in patients with rheumatoid arthritis, further confirms our results and emphasizes the possible role of prolactin on autoimmune diseases and autoimmunity. C. LAVALLE
Rheumatic Diseases Unit, Hospital de Especialidades, Centro Medico La Raza, IMSS, Seris y Zaachila, 02990 Mexico City, Mexico Accepted 27 August 1991 1. Chikanza IC, Panayi GS. Hypothalamic-pituitary mediated modulation of immune function: prolactin as a neuroimmune peptide. Br J Rheumatol 1991;30:203-7. 2. Lavalle C, Loyo E, Paniagua R, et al. Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus. J Rheumatol 1987;14: 268-72. 3. Talal N, Ahmed SA. Immunomodulation by hormones—an area of growing importance. J Rheumatol 1987;14:191-3. 4. Folomeev M, Prokaeva T, Nassonova V. Prolactin levels in men with SLE and RA. J Rheumatol 1990;17:1569-70. 5. Jara-Quezada L, Graef A, Lavalle C. Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus. J Rheumatol 1991;18:349-53. 6. Jara-Quezada L, Lavalle C, Fraga A, etal. Prolactin, immunoregulation and autoimmune diseases. Semin Arthritis Rheum 1991; 20:273-84. 7. Chikanza IC, Pownall R, Panayi GS. Immunoendocrine interactions in the pathogenesis of rheumatoid arthritis: initiating and perpetuating factors? Br J Rheumatol 1990;29(suppl 2):22.
J. L. LENA, J. A. DEL OLMO, J. M. NICOLAS*,
E. VlLLEGAS*, J. MuNOZ-GoMEZ
Rheumatology and * Internal Medicine Units, Hospital Clinic i Prvoncial, Barcelona, Spain Accepted 8 August 1991 1. Harris PJ. Hypertrophic pulmonary osteoarthropathy and human immunodeficiency virus. Ann Intern Med 1988;109(3):250. 2. Bhat S, Heurich A, Vaquer RA, Strashun A, Kamholz S. Hypertrophic osteoarthropathy associated with Pneumocystis carinii pneumonia in AIDS. Chest 1989;96:1208-9. 3. Vaquer RA, Dunn EK, Bhat S, Heurich A, Kamholz S, Strashun A. Reversible pulmonary uptake and hypertrophic
Genetics of Rheumatoid Arthritis SIR—We wish to respond to certain points raised by Lanchbury and co-workers in their letter of August 1990 476
Downloaded from http://rheumatology.oxfordjournals.org/ at Carleton University on August 3, 2015
Pneumocystis carinii Pneumonia causing Hypertrophic Osteoarthropathy SIR—Hypertrophic osteoarthropathy (HO), is a syndrome of chronic proliferative periostitis of the long bones, clubbing of fingers, toes, or both, and oligo- or polysynovitis. The syndrome may be primary (hereditary or idiopathic) or secondary. The secondary forms of HO are most often associated with infectious or neoplasic diseases. Two cases of HO in AIDS patients have recently been described, one associated with HIV infection [1], and the other in a patient suffering from Pneumocystis carinii pneumonia (PCP) [2,3]. We describe a second case of HO associated with PCP. A 33-year-old HIV-antibody positive male, formerly an intravenous drug user, was admitted with a 3-week history of dry cough, progressive dyspnoea and fever. In the previous month the patient complained of polyarthralgia, swelling of the knees and ankles and gradual deformation of the fingers and toes. Physical examination revealed a temperature of 38.2°C, generalized lymphadenopathy, tachypnoea, hepatomegaly, splenomegaly, swelling of the knees and ankles, and clubbing of the digits. Laboratory tests showed a Westergren sedimentation rate of 90mm/h, a haemoglobin level of 10.7 g/dl, and a total leucocyte count of 19.2 x 109/l. Arterial blood gas levels were pH 7.42, Fo 2 79 mmHg, Pco 2 31 mmHg. The chest X-ray revealed a pattern of bilateral alveolar interstitial involvement. A fibreoptic bronchoscopy was performed and Gomori methenamine silver staining of cytocentrifuge bronchoalveolar lavage (BAL) fluid preparations showed Pneumocystis carinii cysts. Bone radiographs revealed periosteal elevation and subperiosteal new bone formation in the diaphysis of the ulna, radius, tibia and fibula, with increased uptake in these regions in the 99Tc bone scintigram. A non-inflammatory synovial fluid was obtained from the left knee. Bacterial, mycobacterial and fungal cultures of sputum, blood, BAL and synovial fluid were all negative. The patient was treated with parenteral pentamidine with clinicoradiological resolution of the pneumonia and subsequent disappearance of osteoarticular symptoms. The symptom complex of the patient, the fact that no other illness could be detected and the disappearance of the joint symptoms following the resolution of PCP enable us to talk about HO, or more correctly, 'pseudohypertrophic osteoarthropathy', associated with PCP, thus adding a new entity to the possible causes of secondary hypertrophic osteoarthropathy.
LETTERS TO THE EDITOR
D. M. GRENNAN, M. C. HILLARBY
Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD Accepted 28 August 1991 1. Lanchbury T, Sakkar L, Welsh K, Panayi G. Genetics of rheumatoid arthritis. Br J Rheumatol 1991:30:319-20. 2. Sansom DM, Bidwell T, Maddison P, Campion G, Klouda P, Bradley B. HLA DQA and DQB restriction fragment length polymorphisms associated with rheumatoid arthritis. Human Immunol 1987;19:269-79. 3. So ARL, Wamu C, Sansom D. Walport M. DQB polymorphisms and genetic susceptibility to Felty's syndrome. Arthritis Rheum 1988;31:990-4. 4. Hillarby MC, Clarkson R, Grennan DM, et al. Immunogenetic heterogenity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. Br J Rheumatol 1991 ;30:5—9. 5. Clarkson R, Bate AS, Grennan D, et al. DQw7 and the C4A null allele in rheumatoid arthritis and Felty's syndrome. Ann Rheum Dis 1990;49:976-9. Does the Weather affect the Osteoarthritic Patient?
SIR—Changing weather patterns have often been blamed by our osteoarthritic patients for the wide daily variety in their symptoms of pain and stiffness. Despite the severity of their disease, our joint replacement patients frequently offered this information. With this in mind we conducted a study over a 6-month period where aspects of the weather could be compared with the patient's symptoms. While there have been some inconclusive papers from other parts of Europe and North America [1-5], the UK has surprisingly escaped attention. Fifty-three consecutive patients completed a questionnaire for 30 days each, over the summer and winter months of 1990. A rating scale was used each day to assess the generalized feelings of pain and stiffness in the joint which was due to be replaced. At the same time on those days atmospheric pressure and humidity were measured. Statistical analysis using Wilcoxon's matched pairs signed ranks test found no correlation between our patients' symptoms and these weather variables. The conclusions we have reached are naturally tightly
limited. Changes in temperature could not be assessed as each patient's home environment would have differed, giving us erroneous results, whereas barometric pressure and humidity are not subject to these variations. Also, the influence of rapidly changing weather patterns is extremely difficult to assess. Nevertheless we did find that it was remarkable how constant patients' daily symptoms were despite marked changes in our weather variables. There is no doubt room for further study particularly in the more 'inflammatory' patients such as the early rheumatoid . Unfortunately and inevitably most of our patients have end staged disease. We would welcome other people's experience. A. M. CLARKE, J. NICHOLL
King Edward VII Orthopaedic Hospital, Sheffield and Medical Care Research Unit, Sheffield University Medical School Accepted 29 August 1991 1. Laborde JM, Dando WA, Powers MJ. Influence of weather on ostcoarthritics. Soc Sci Med 1986;23:549-54. 2. Sibley JT. Weather and arthritis symptoms. J Rheumatol 1985;'l2:707-10. 3. Rasker J, Peters HJG, Boon KL. Influence of weather on stiffness and force in patients with rheumatoid arthritis. Scand J Rheumatol 1986;15:27-36. 4. Patberg WR, Nienhuis RLF, Veringa F. Relation between meteorological factors and pain in rheumatoid arthritis in a marine climate. J Rheumatol 1985:12:711-15. 5. Guedj D, Weinberger A. Effect of weather conditions on rheumatic patients. Ann Rheum Dis 1990:49:158-69. Assessment of Disability in Male and Female Rheumatoid Patients
SIR—We were interested to read the report by Thompson and Pegley [1] on their survey of male and female rheumatoid outpatients using the Stanford Health Assessment Questionnaire. The significant difference in functional status between the sexes is interesting, as apart from nodules being commoner in the men, there were no significant differences between the two groups in other disease parameters. This raises the question whether the subgroup of, so-called, rheumatoid arthritis robustus [2] may be more common than is appreciated. We have recently analysed the results of the Health Assessment Questionnaire in 100 patients with rheumatoid arthritis attending our unit over a 4-week period; there were 20 men and 80 women. Our results support those of Thompson and Pegley: the mean HAQ score in the men was 1.27 (SD 0.83) and in the women was 1.69 (SD 0.71) (P-cO.05). Perhaps less surprisingly the grip strength in the males was substantially greater than the females (217 mmHg, SD 80.5 and 109 mmHg, SD 50.6). We agree that the observable difference in disability from rheumatoid arthritis in men and women is worthy of further study. F. MCKENNA, A. TRACEY, J. HAYES
Trafford General Hospital, Rheumatic Diseases Unit, Davyhulme, Manchester M31 3SL Accepted 29 August 1991 1. Thompson PW, Pegley FS. A comparison of disability measured by the Stanford Health Assessment Questionnaire Disability Scales (HAQ) in male and female rheumatoid outpatients. BrJ Rheumatol 1991;30:298-300. 2. de Haas WHD, DcBoer W, Griffiocn F. Oosten-Elst P. Rheumatoid arthritis of the robust reaction type. Ann Rheum Dis 1974;33:81-4. Radionuclide Angiography
SIR—We describe a technique which uses radionuclide
Downloaded from http://rheumatology.oxfordjournals.org/ at Carleton University on August 3, 2015
[1]. In their letter Lanchbury and co-workers discuss the MHC association in Felty's syndrome with the DQB encoded variant DQw7 as described by several groups [2, 3]. Lanchbury and co-workers suggest that this association is secondary to a primary association at the DRB1 locus with Dw4. We have examined this possibility in a previous study [4] and have compared Dw4 frequencies in DR4 positive subjects with rheumatoid arthritis, rheumatoid arthritis and Felty's syndrome and controls. In this study the Dw4 frequency in these DR4 positive subjects was not significantly increased in the Felty's group although DQw7 was, so that the DQ association in Felty's syndrome is unlikely to be secondary to a primary effect at DRB1 and the results suggest that MHC genes at loci outside DRB1 may influence susceptibility to certain rheumatoid disease subgroups or may have a disease modifying effect. Felty's syndrome also shows an association with the class III C4B null allele and an association with the haplotype B44-Bf*s-C4A*3-C4B*QO-DR4-DQw7 and we have previously suggested that this haplotypic association represents an interaction between variants at several loci within the HLA region [5]. Different MHC associations are seen in other extra-articular subgroups [4] so that the clinical heterogeneity of rheumatoid disease is reflected in its immunogenetic heterogeneity.
477
LETTERS TO THE EDITOR pulmonary osteoarthropathic distribution of technetium-99m methylene diphosphonate in a case of Pneumocystis carinii pneumonia. J Nucl Med 1989;30:1563-7. Role of Prolactin in Autoimmune Diseases and Autoimmunity SIR—We have read with interest the excellent review about hypothalamic-pituitary mediated modulation of immune function: prolactin as a neuroimmune peptide, written by Chikanza and Panayi [1]. Although one of our articles presented in an American Rheumatism Association Congress in 1988 was cited in this review, the first published article that associates prolactin with autoimmune diseases (SLE) appeared in 1987 [2]. This article prompted an editorial written by Talal and Ahmed [3] that emphasized the importance of prolactin as an immunomodulator peptide. In 1990, Folomeev et al. [4] were able to confirm our results of hyperprolactinaemia in male patients with SLE. More recently, our group published an article about prolactin and gonadal hormones during pregnancy in SLE [5]. Higher serum prolactin levels were found in pregnant patients with SLE than those found in pregnant patients with RA or otherwise healthy pregnant controls. In April 1991, a review of prolactin, immunoregulation, and autoimmune diseases appeared in Seminars in Arthritis and Rheumatism [6]. This review was written by the Division of Rheumatology and Endocrinology of the University of South Florida and also by our group; it was based on our previous findings and included a review of the literature. The study done by Panayi etal. [7] in patients with rheumatoid arthritis, further confirms our results and emphasizes the possible role of prolactin on autoimmune diseases and autoimmunity. C. LAVALLE
Rheumatic Diseases Unit, Hospital de Especialidades, Centro Medico La Raza, IMSS, Seris y Zaachila, 02990 Mexico City, Mexico Accepted 27 August 1991 1. Chikanza IC, Panayi GS. Hypothalamic-pituitary mediated modulation of immune function: prolactin as a neuroimmune peptide. Br J Rheumatol 1991;30:203-7. 2. Lavalle C, Loyo E, Paniagua R, et al. Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus. J Rheumatol 1987;14: 268-72. 3. Talal N, Ahmed SA. Immunomodulation by hormones—an area of growing importance. J Rheumatol 1987;14:191-3. 4. Folomeev M, Prokaeva T, Nassonova V. Prolactin levels in men with SLE and RA. J Rheumatol 1990;17:1569-70. 5. Jara-Quezada L, Graef A, Lavalle C. Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus. J Rheumatol 1991;18:349-53. 6. Jara-Quezada L, Lavalle C, Fraga A, etal. Prolactin, immunoregulation and autoimmune diseases. Semin Arthritis Rheum 1991; 20:273-84. 7. Chikanza IC, Pownall R, Panayi GS. Immunoendocrine interactions in the pathogenesis of rheumatoid arthritis: initiating and perpetuating factors? Br J Rheumatol 1990;29(suppl 2):22.
J. L. LENA, J. A. DEL OLMO, J. M. NICOLAS*,
E. VlLLEGAS*, J. MuNOZ-GoMEZ
Rheumatology and * Internal Medicine Units, Hospital Clinic i Prvoncial, Barcelona, Spain Accepted 8 August 1991 1. Harris PJ. Hypertrophic pulmonary osteoarthropathy and human immunodeficiency virus. Ann Intern Med 1988;109(3):250. 2. Bhat S, Heurich A, Vaquer RA, Strashun A, Kamholz S. Hypertrophic osteoarthropathy associated with Pneumocystis carinii pneumonia in AIDS. Chest 1989;96:1208-9. 3. Vaquer RA, Dunn EK, Bhat S, Heurich A, Kamholz S, Strashun A. Reversible pulmonary uptake and hypertrophic
Genetics of Rheumatoid Arthritis SIR—We wish to respond to certain points raised by Lanchbury and co-workers in their letter of August 1990 476
Downloaded from http://rheumatology.oxfordjournals.org/ at Carleton University on August 3, 2015
Pneumocystis carinii Pneumonia causing Hypertrophic Osteoarthropathy SIR—Hypertrophic osteoarthropathy (HO), is a syndrome of chronic proliferative periostitis of the long bones, clubbing of fingers, toes, or both, and oligo- or polysynovitis. The syndrome may be primary (hereditary or idiopathic) or secondary. The secondary forms of HO are most often associated with infectious or neoplasic diseases. Two cases of HO in AIDS patients have recently been described, one associated with HIV infection [1], and the other in a patient suffering from Pneumocystis carinii pneumonia (PCP) [2,3]. We describe a second case of HO associated with PCP. A 33-year-old HIV-antibody positive male, formerly an intravenous drug user, was admitted with a 3-week history of dry cough, progressive dyspnoea and fever. In the previous month the patient complained of polyarthralgia, swelling of the knees and ankles and gradual deformation of the fingers and toes. Physical examination revealed a temperature of 38.2°C, generalized lymphadenopathy, tachypnoea, hepatomegaly, splenomegaly, swelling of the knees and ankles, and clubbing of the digits. Laboratory tests showed a Westergren sedimentation rate of 90mm/h, a haemoglobin level of 10.7 g/dl, and a total leucocyte count of 19.2 x 109/l. Arterial blood gas levels were pH 7.42, Fo 2 79 mmHg, Pco 2 31 mmHg. The chest X-ray revealed a pattern of bilateral alveolar interstitial involvement. A fibreoptic bronchoscopy was performed and Gomori methenamine silver staining of cytocentrifuge bronchoalveolar lavage (BAL) fluid preparations showed Pneumocystis carinii cysts. Bone radiographs revealed periosteal elevation and subperiosteal new bone formation in the diaphysis of the ulna, radius, tibia and fibula, with increased uptake in these regions in the 99Tc bone scintigram. A non-inflammatory synovial fluid was obtained from the left knee. Bacterial, mycobacterial and fungal cultures of sputum, blood, BAL and synovial fluid were all negative. The patient was treated with parenteral pentamidine with clinicoradiological resolution of the pneumonia and subsequent disappearance of osteoarticular symptoms. The symptom complex of the patient, the fact that no other illness could be detected and the disappearance of the joint symptoms following the resolution of PCP enable us to talk about HO, or more correctly, 'pseudohypertrophic osteoarthropathy', associated with PCP, thus adding a new entity to the possible causes of secondary hypertrophic osteoarthropathy.
LETTERS TO THE EDITOR
D. M. GRENNAN, M. C. HILLARBY
Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD Accepted 28 August 1991 1. Lanchbury T, Sakkar L, Welsh K, Panayi G. Genetics of rheumatoid arthritis. Br J Rheumatol 1991:30:319-20. 2. Sansom DM, Bidwell T, Maddison P, Campion G, Klouda P, Bradley B. HLA DQA and DQB restriction fragment length polymorphisms associated with rheumatoid arthritis. Human Immunol 1987;19:269-79. 3. So ARL, Wamu C, Sansom D. Walport M. DQB polymorphisms and genetic susceptibility to Felty's syndrome. Arthritis Rheum 1988;31:990-4. 4. Hillarby MC, Clarkson R, Grennan DM, et al. Immunogenetic heterogenity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. Br J Rheumatol 1991 ;30:5—9. 5. Clarkson R, Bate AS, Grennan D, et al. DQw7 and the C4A null allele in rheumatoid arthritis and Felty's syndrome. Ann Rheum Dis 1990;49:976-9. Does the Weather affect the Osteoarthritic Patient?
SIR—Changing weather patterns have often been blamed by our osteoarthritic patients for the wide daily variety in their symptoms of pain and stiffness. Despite the severity of their disease, our joint replacement patients frequently offered this information. With this in mind we conducted a study over a 6-month period where aspects of the weather could be compared with the patient's symptoms. While there have been some inconclusive papers from other parts of Europe and North America [1-5], the UK has surprisingly escaped attention. Fifty-three consecutive patients completed a questionnaire for 30 days each, over the summer and winter months of 1990. A rating scale was used each day to assess the generalized feelings of pain and stiffness in the joint which was due to be replaced. At the same time on those days atmospheric pressure and humidity were measured. Statistical analysis using Wilcoxon's matched pairs signed ranks test found no correlation between our patients' symptoms and these weather variables. The conclusions we have reached are naturally tightly
limited. Changes in temperature could not be assessed as each patient's home environment would have differed, giving us erroneous results, whereas barometric pressure and humidity are not subject to these variations. Also, the influence of rapidly changing weather patterns is extremely difficult to assess. Nevertheless we did find that it was remarkable how constant patients' daily symptoms were despite marked changes in our weather variables. There is no doubt room for further study particularly in the more 'inflammatory' patients such as the early rheumatoid . Unfortunately and inevitably most of our patients have end staged disease. We would welcome other people's experience. A. M. CLARKE, J. NICHOLL
King Edward VII Orthopaedic Hospital, Sheffield and Medical Care Research Unit, Sheffield University Medical School Accepted 29 August 1991 1. Laborde JM, Dando WA, Powers MJ. Influence of weather on ostcoarthritics. Soc Sci Med 1986;23:549-54. 2. Sibley JT. Weather and arthritis symptoms. J Rheumatol 1985;'l2:707-10. 3. Rasker J, Peters HJG, Boon KL. Influence of weather on stiffness and force in patients with rheumatoid arthritis. Scand J Rheumatol 1986;15:27-36. 4. Patberg WR, Nienhuis RLF, Veringa F. Relation between meteorological factors and pain in rheumatoid arthritis in a marine climate. J Rheumatol 1985:12:711-15. 5. Guedj D, Weinberger A. Effect of weather conditions on rheumatic patients. Ann Rheum Dis 1990:49:158-69. Assessment of Disability in Male and Female Rheumatoid Patients
SIR—We were interested to read the report by Thompson and Pegley [1] on their survey of male and female rheumatoid outpatients using the Stanford Health Assessment Questionnaire. The significant difference in functional status between the sexes is interesting, as apart from nodules being commoner in the men, there were no significant differences between the two groups in other disease parameters. This raises the question whether the subgroup of, so-called, rheumatoid arthritis robustus [2] may be more common than is appreciated. We have recently analysed the results of the Health Assessment Questionnaire in 100 patients with rheumatoid arthritis attending our unit over a 4-week period; there were 20 men and 80 women. Our results support those of Thompson and Pegley: the mean HAQ score in the men was 1.27 (SD 0.83) and in the women was 1.69 (SD 0.71) (P-cO.05). Perhaps less surprisingly the grip strength in the males was substantially greater than the females (217 mmHg, SD 80.5 and 109 mmHg, SD 50.6). We agree that the observable difference in disability from rheumatoid arthritis in men and women is worthy of further study. F. MCKENNA, A. TRACEY, J. HAYES
Trafford General Hospital, Rheumatic Diseases Unit, Davyhulme, Manchester M31 3SL Accepted 29 August 1991 1. Thompson PW, Pegley FS. A comparison of disability measured by the Stanford Health Assessment Questionnaire Disability Scales (HAQ) in male and female rheumatoid outpatients. BrJ Rheumatol 1991;30:298-300. 2. de Haas WHD, DcBoer W, Griffiocn F. Oosten-Elst P. Rheumatoid arthritis of the robust reaction type. Ann Rheum Dis 1974;33:81-4. Radionuclide Angiography
SIR—We describe a technique which uses radionuclide
Downloaded from http://rheumatology.oxfordjournals.org/ at Carleton University on August 3, 2015
[1]. In their letter Lanchbury and co-workers discuss the MHC association in Felty's syndrome with the DQB encoded variant DQw7 as described by several groups [2, 3]. Lanchbury and co-workers suggest that this association is secondary to a primary association at the DRB1 locus with Dw4. We have examined this possibility in a previous study [4] and have compared Dw4 frequencies in DR4 positive subjects with rheumatoid arthritis, rheumatoid arthritis and Felty's syndrome and controls. In this study the Dw4 frequency in these DR4 positive subjects was not significantly increased in the Felty's group although DQw7 was, so that the DQ association in Felty's syndrome is unlikely to be secondary to a primary effect at DRB1 and the results suggest that MHC genes at loci outside DRB1 may influence susceptibility to certain rheumatoid disease subgroups or may have a disease modifying effect. Felty's syndrome also shows an association with the class III C4B null allele and an association with the haplotype B44-Bf*s-C4A*3-C4B*QO-DR4-DQw7 and we have previously suggested that this haplotypic association represents an interaction between variants at several loci within the HLA region [5]. Different MHC associations are seen in other extra-articular subgroups [4] so that the clinical heterogeneity of rheumatoid disease is reflected in its immunogenetic heterogeneity.
477
