LETTERS long term haemodialysis patients. Proc Eur Dial Transplant ASSOC21~291-295, 1985 6 . Gejyo F, Yamada T, Odani S, Nakagawa Y, Kunitomo T, Kataoka H, Suzuki M, Himarawa Y , Shirahama T, Cohen AS, Schmid K: A new form of amyloid protein associated with hemodialysis was identified as p2 microglobulin. Biochem
Biophys Res Commun 129:701-706, 1985 7. Vandenbroucke J, Jadoul M, Maldague B, Huaux JP, Noel H, van Ypersele de Strihou C: Possible role of dialysis membrane characteristics in amyloid osteoarthropathy. Lancet 11: 12101211, 1986 8. Gaucher A, Kessler M, Netter P, Azoulay E, Pert P, Mur JM: Dialysis arthropathy: the effect of age. J Rheumatol 15:
1880-1881, 1988 9. Netter P, Kessler M, Gaucher A, Gillet P, Delons S, Burnel D, Benoit J , Got C: Aluminum and dialysis arthropathy. Lancet IL886-887, 1988 10. Cary NRB, Sethi D, Brown A, Erhardt CC, Woodrow DF, Gower PE: Dialysis arthropathy: amyloid or iron? Br Med J 293~1392-1394. 1986
Cricoarytenoid synovitis in ankylosing spondylitis To the Editor: The cricoarytenoid joint is a diarthrodial articulation with a ligamentous capsule lined by synovial membrane (1). Involvement of this joint in rheumatoid arthritis (RA) has been well documented clinically and pathologically ( I-3), whereas cricoarytenoid joint synovitis is an unusual feature of ankylosing spondylitis (4-7). We present herein the clinicopathologic features of severe cricoarytenoid synovitis in a patient with longstanding ankylosing spondylitis. The patient, a 79-year-old white man, was diagnosed as having ankylosing spondylitis at age 25, on the basis of persistent back pain and stiffness. Over the next several years, spine radiographs showed evidence of complete ankylosis at both sacroiliac joints and the entire lumbosacral, thoracic, and cervical spines. His HLA-B27 status was never ascertained. Four years prior to admission, the patient noted progressive difficulty ambulating and changes in bowel and bladder habits. He underwent a cervical laminectomy for spinal stenosis; however, neurologic symptoms persisted. Two months prior to admission, he developed dysphagia and a productive cough, and he noted a 20-lb weight loss. Results of a chest radiograph, endoscopy of the upper gastrointestinal tract, and a barium swallow were reported as normal. A few weeks later, he developed laryngeal stridor and hypotension and was admitted to another hospital. A laryngoscopy revealed arytenoid edema and right vocal cord paralysis. He was treated with high doses of intravenous corticosteroids, with resolution of his stridor. Steroids were subsequently tapered, and the stridor recurred, along with a new right lower lobe infiltrate. A laryngoscopy revealed bilateral vocal cord paralysis and a posterior cricoid ulcerative lesion extending to the hypopharynx. A thyrocricoid tracheostomy was performed, which relieved the airways obstruction. A few days later, the patient developed hypotension, oliguria, lethargy, and an elevation of his white blood cell count to 18,000 cells/mm3. Despite the initiation of broad-spectrum antibiotic and antifungal therapy, his condition continued to deteriorate, and he died shortly thereafter.
Figure 1. Low power photomicroscopic view of the left cricoarytenoid joint. A small amount of articular cartilage remains in the arytenoid area (seen on the right);the articular surface of the cricoid cartilage is denuded (seen on the left). Both cartilages show extensive calcification (arrowheads). The joint space is filled with dark hemorrhagic material, fibrin, and inflammatory cells (original magnification x 10).
At autopsy, there was evidence of a severe chronic, active cricoarytenoiditis with inflammatory obliteration of the cricoarytenoid joints bilaterally. The intense inflammatory reaction surrounding the laryngeal cartilages in the region of the cricoarytenoid joints led to ulceration of the overlying laryngeal and esophageal mucosae (Figure 1). No tumor was identified, and special stains for organisms were negative. An acute necrotizing aspiration pneumonia involving the right upper and middle lobes was also identified and was the immediate cause of death. A compilation of previously reported cases of cricoarytenoid synovitis in association with ankylosing spondylitis (4-7) indicates that patients had longstanding disease (mean 26.5 years) with extensive spinal ankylosis including the cervical spine. Cricoarytenoid synovitis resulted in some degree of airways compromise in 5 of 6 patients. Initial manifestations included dyspnea and hoarseness, stridor, and throat pain. Three patients developed acute respiratory failure, and 2 patients aspirated. The management of cricoarytenoid synovitis in ankylosing spondylitis included tracheostomy (3 of 6 patients), arytenoidectomy ( 1 of 6), and the use of corticosteroids either orally or intraarticularly. Bienenstock et al (1) correlated the results of cricoarytenoid joint laryngoscopic examination with clinical symptoms in patients with RA. When both cricoarytenoid joints were involved, bowing of the vocal cords was seen during the inspiratory phase of respiration. Chronic unilateral disease resulted in slight hoarseness andlor dyspnea on exertion, whereas dyspnea would predominate with bilateral cricoarytenoid joint disease. Fixation of the vocal cords in adduction resulted in hoarseness or aphonia. The pathologic findings in our patient, of extensive inflammatory destruction of the cricoarytenoid joints with “spillover” of the process into adjacent tissues such as the
605
LETTERS
larynx and esophageal mucosa, are unusual. Histopathologic analysis of the only other 2 cricoarytenoid joint specimens obtained revealed chronic inflammation and calcified cartilage in both (4,7). Severe destructive changes similar to the findings in our patient were not noted. A case of cricoarytenoid synovitis with clinical and histopathologic features reminiscent of those in our patient was described in a patient with RA (8). This patient was treated successfully by total laryngectomy to enable the removal of the esophageal ulcerations and to establish deglutition. Cricoarytenoid synovitis is an unusual complication of longstanding ankylosing spondylitis. It should be considered in patients who report dyspnea, hoarseness, or throat pain. It is conceivable that early diagnosis and intervention with steroids or tracheostomy may preclude the development of life-threatening complications. Simon M. Helfgott, MD Patrick A. Treseler, MD. PhD Harvard Medical School Boston, M A
I . Bienenstock H, Ehrlich GE. Freyberg RH: Rheumatoid arthritis of the cricoarytenoid joint: a clinicopathologic study. Arthritis Rheum 6:48-62. 1963 2. Lofgren RH, Montgomery WW: Incidence of laryngeal involvement in rheumatoid arthritis. N Engl J Med 267: 193-195. 1%2 3. Grossrnan A, Martin JR. Root HS: Rheumatoid arthritis of the cricoarytenoid joint. Laryngoscope 71530-544, 1961 4. Wojtulewski JA. Sturrock RD. Branfoot AC. Hart FD: Cricoarytenoid arthritis in ankylosing spondylitis. Br Med J 3: 145-146, 1973 5. Berendes J, Miehlke A: A rare ankylosis of the cricoarytenoid joints. Arch Otolaryngol Head Neck Surg 98:6345, 1973 6. Bienenstock H, Lanyi VF: Cricoarytenoid arthritis in a patient with ankylosing spondylitis. Arch Otolaryngol Head Neck Surg 103:738-739, 1977 7. Libby DM, Schley S, Smith JP: Cricoarytenoid arthritis in ankylosing spondylitis. Chest 80:641443. 1981 8. Montgomery WW. Goodman MI: Rheumatoid cricoarytenoid arthritis complicated by upper esophageal ulcerations. Ann Otol Rhino1 Laryngol 895-8, 1980
Comment on the article by Singh et al To the Editor: The data from the American Rheumatism Association Medical Information System (ARAMIS) about the lack of azathioprine-induced neoplasia (Singh G , Fries JF, Spitz P, Williams CA: Toxic effects of azathioprine in rheumatoid arthritis: a national post-marketing perspective. Arthritis Rheum 322337443, 1989) are, I’m sure, statistically unimpeachable. However, I question their clinical significance. The duration of therapy and, I believe. followup was 20.8 ( 21.1 SEM) months. The authors of studies that have shown a risk of drug-induced neoplasia have pointed out that the increased risk may, not be seen until many years later (Baker GL, Kahl LE, Zee BC, Stoker BL, Agarwal AK, Medsger TA: Malignancy following treatment of rheumatoid arthritis with cyclophosphamide: long term case control follow up study. Am J Med 83:l-9, 1987). While the discussion following the ARAMIS results suggests that a longer followup is
necessary to “provide an unequivocal answer,” I am concerned that shorter studies merely muddy the waters by adding to the list of referenced studies that have failed to demonstrate an association. A. S. Russell, F.RCP(C) University of Alberta Edmonton, Alberta, Canada
To the Editor: We agree with Dr. Russell’s comments, and we addressed his concerns in our article, which was an initial report of a longitudinal prospective study of a large number of azathioprine-treated patients. Definitive long-term outcome studies, of course, require long-term followup, and we will subsequently report further on this cohort. Large numbers of patients are required because there is a substantial background frequency of the events that are being surveyed, and thus, anecdotal reports are of no use. The findings of the preliminary study, with the largest number of patient-years of observation yet examined, are encouraging. Determination of the ultimate comparative toxicity of drugs over a longer time period is complicated indeed, since it depends upon accurate measurement of certain target events as well as ascertainment of events that might possibly have been avoided by the use of a particular agent, such as decreased corticosteroid-related atherosclerosis, decreased gold-induced thrombocytopenia, decreased nonsteroidal antiinflammatory drug-related gastrointestinal hemorrhage, and many others. We believe that the only way to examine these questions is with rigorously controlled, prospective, high-quality. long-term data. Of interest, the data collection process and numbers reported would have easily been sufficient to identify any cases of myelocytic leukemia following cyclophosphamide therapy; the prevalence of that well-recognized complication is obviously much greater than any similar risk that may or may not be present with azathioprine. James F. Fries, MD Stanford Universi/y Medical Center Stanford, C A
Comment on the article by Lockshin To the Editor: We wish to take issue with statements made by Dr. Lockshin in his article dealing with pregnancy and its effects on systemic lupus erythematosus (SLE) (Lockshin MD: Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 32:665-670, 1989). While we applaud the attempt to study patients prospectively, we believe the question of whether pregnancy produces a flare of disease activity in SLE patients can only be answered by studying the same patient for at least 2 years prior to pregnancy, during pregnancy, and 1 year postpartum, thus using the patient as her own control. Lockshin’s investiga-
Biophys Res Commun 129:701-706, 1985 7. Vandenbroucke J, Jadoul M, Maldague B, Huaux JP, Noel H, van Ypersele de Strihou C: Possible role of dialysis membrane characteristics in amyloid osteoarthropathy. Lancet 11: 12101211, 1986 8. Gaucher A, Kessler M, Netter P, Azoulay E, Pert P, Mur JM: Dialysis arthropathy: the effect of age. J Rheumatol 15:
1880-1881, 1988 9. Netter P, Kessler M, Gaucher A, Gillet P, Delons S, Burnel D, Benoit J , Got C: Aluminum and dialysis arthropathy. Lancet IL886-887, 1988 10. Cary NRB, Sethi D, Brown A, Erhardt CC, Woodrow DF, Gower PE: Dialysis arthropathy: amyloid or iron? Br Med J 293~1392-1394. 1986
Cricoarytenoid synovitis in ankylosing spondylitis To the Editor: The cricoarytenoid joint is a diarthrodial articulation with a ligamentous capsule lined by synovial membrane (1). Involvement of this joint in rheumatoid arthritis (RA) has been well documented clinically and pathologically ( I-3), whereas cricoarytenoid joint synovitis is an unusual feature of ankylosing spondylitis (4-7). We present herein the clinicopathologic features of severe cricoarytenoid synovitis in a patient with longstanding ankylosing spondylitis. The patient, a 79-year-old white man, was diagnosed as having ankylosing spondylitis at age 25, on the basis of persistent back pain and stiffness. Over the next several years, spine radiographs showed evidence of complete ankylosis at both sacroiliac joints and the entire lumbosacral, thoracic, and cervical spines. His HLA-B27 status was never ascertained. Four years prior to admission, the patient noted progressive difficulty ambulating and changes in bowel and bladder habits. He underwent a cervical laminectomy for spinal stenosis; however, neurologic symptoms persisted. Two months prior to admission, he developed dysphagia and a productive cough, and he noted a 20-lb weight loss. Results of a chest radiograph, endoscopy of the upper gastrointestinal tract, and a barium swallow were reported as normal. A few weeks later, he developed laryngeal stridor and hypotension and was admitted to another hospital. A laryngoscopy revealed arytenoid edema and right vocal cord paralysis. He was treated with high doses of intravenous corticosteroids, with resolution of his stridor. Steroids were subsequently tapered, and the stridor recurred, along with a new right lower lobe infiltrate. A laryngoscopy revealed bilateral vocal cord paralysis and a posterior cricoid ulcerative lesion extending to the hypopharynx. A thyrocricoid tracheostomy was performed, which relieved the airways obstruction. A few days later, the patient developed hypotension, oliguria, lethargy, and an elevation of his white blood cell count to 18,000 cells/mm3. Despite the initiation of broad-spectrum antibiotic and antifungal therapy, his condition continued to deteriorate, and he died shortly thereafter.
Figure 1. Low power photomicroscopic view of the left cricoarytenoid joint. A small amount of articular cartilage remains in the arytenoid area (seen on the right);the articular surface of the cricoid cartilage is denuded (seen on the left). Both cartilages show extensive calcification (arrowheads). The joint space is filled with dark hemorrhagic material, fibrin, and inflammatory cells (original magnification x 10).
At autopsy, there was evidence of a severe chronic, active cricoarytenoiditis with inflammatory obliteration of the cricoarytenoid joints bilaterally. The intense inflammatory reaction surrounding the laryngeal cartilages in the region of the cricoarytenoid joints led to ulceration of the overlying laryngeal and esophageal mucosae (Figure 1). No tumor was identified, and special stains for organisms were negative. An acute necrotizing aspiration pneumonia involving the right upper and middle lobes was also identified and was the immediate cause of death. A compilation of previously reported cases of cricoarytenoid synovitis in association with ankylosing spondylitis (4-7) indicates that patients had longstanding disease (mean 26.5 years) with extensive spinal ankylosis including the cervical spine. Cricoarytenoid synovitis resulted in some degree of airways compromise in 5 of 6 patients. Initial manifestations included dyspnea and hoarseness, stridor, and throat pain. Three patients developed acute respiratory failure, and 2 patients aspirated. The management of cricoarytenoid synovitis in ankylosing spondylitis included tracheostomy (3 of 6 patients), arytenoidectomy ( 1 of 6), and the use of corticosteroids either orally or intraarticularly. Bienenstock et al (1) correlated the results of cricoarytenoid joint laryngoscopic examination with clinical symptoms in patients with RA. When both cricoarytenoid joints were involved, bowing of the vocal cords was seen during the inspiratory phase of respiration. Chronic unilateral disease resulted in slight hoarseness andlor dyspnea on exertion, whereas dyspnea would predominate with bilateral cricoarytenoid joint disease. Fixation of the vocal cords in adduction resulted in hoarseness or aphonia. The pathologic findings in our patient, of extensive inflammatory destruction of the cricoarytenoid joints with “spillover” of the process into adjacent tissues such as the
605
LETTERS
larynx and esophageal mucosa, are unusual. Histopathologic analysis of the only other 2 cricoarytenoid joint specimens obtained revealed chronic inflammation and calcified cartilage in both (4,7). Severe destructive changes similar to the findings in our patient were not noted. A case of cricoarytenoid synovitis with clinical and histopathologic features reminiscent of those in our patient was described in a patient with RA (8). This patient was treated successfully by total laryngectomy to enable the removal of the esophageal ulcerations and to establish deglutition. Cricoarytenoid synovitis is an unusual complication of longstanding ankylosing spondylitis. It should be considered in patients who report dyspnea, hoarseness, or throat pain. It is conceivable that early diagnosis and intervention with steroids or tracheostomy may preclude the development of life-threatening complications. Simon M. Helfgott, MD Patrick A. Treseler, MD. PhD Harvard Medical School Boston, M A
I . Bienenstock H, Ehrlich GE. Freyberg RH: Rheumatoid arthritis of the cricoarytenoid joint: a clinicopathologic study. Arthritis Rheum 6:48-62. 1963 2. Lofgren RH, Montgomery WW: Incidence of laryngeal involvement in rheumatoid arthritis. N Engl J Med 267: 193-195. 1%2 3. Grossrnan A, Martin JR. Root HS: Rheumatoid arthritis of the cricoarytenoid joint. Laryngoscope 71530-544, 1961 4. Wojtulewski JA. Sturrock RD. Branfoot AC. Hart FD: Cricoarytenoid arthritis in ankylosing spondylitis. Br Med J 3: 145-146, 1973 5. Berendes J, Miehlke A: A rare ankylosis of the cricoarytenoid joints. Arch Otolaryngol Head Neck Surg 98:6345, 1973 6. Bienenstock H, Lanyi VF: Cricoarytenoid arthritis in a patient with ankylosing spondylitis. Arch Otolaryngol Head Neck Surg 103:738-739, 1977 7. Libby DM, Schley S, Smith JP: Cricoarytenoid arthritis in ankylosing spondylitis. Chest 80:641443. 1981 8. Montgomery WW. Goodman MI: Rheumatoid cricoarytenoid arthritis complicated by upper esophageal ulcerations. Ann Otol Rhino1 Laryngol 895-8, 1980
Comment on the article by Singh et al To the Editor: The data from the American Rheumatism Association Medical Information System (ARAMIS) about the lack of azathioprine-induced neoplasia (Singh G , Fries JF, Spitz P, Williams CA: Toxic effects of azathioprine in rheumatoid arthritis: a national post-marketing perspective. Arthritis Rheum 322337443, 1989) are, I’m sure, statistically unimpeachable. However, I question their clinical significance. The duration of therapy and, I believe. followup was 20.8 ( 21.1 SEM) months. The authors of studies that have shown a risk of drug-induced neoplasia have pointed out that the increased risk may, not be seen until many years later (Baker GL, Kahl LE, Zee BC, Stoker BL, Agarwal AK, Medsger TA: Malignancy following treatment of rheumatoid arthritis with cyclophosphamide: long term case control follow up study. Am J Med 83:l-9, 1987). While the discussion following the ARAMIS results suggests that a longer followup is
necessary to “provide an unequivocal answer,” I am concerned that shorter studies merely muddy the waters by adding to the list of referenced studies that have failed to demonstrate an association. A. S. Russell, F.RCP(C) University of Alberta Edmonton, Alberta, Canada
To the Editor: We agree with Dr. Russell’s comments, and we addressed his concerns in our article, which was an initial report of a longitudinal prospective study of a large number of azathioprine-treated patients. Definitive long-term outcome studies, of course, require long-term followup, and we will subsequently report further on this cohort. Large numbers of patients are required because there is a substantial background frequency of the events that are being surveyed, and thus, anecdotal reports are of no use. The findings of the preliminary study, with the largest number of patient-years of observation yet examined, are encouraging. Determination of the ultimate comparative toxicity of drugs over a longer time period is complicated indeed, since it depends upon accurate measurement of certain target events as well as ascertainment of events that might possibly have been avoided by the use of a particular agent, such as decreased corticosteroid-related atherosclerosis, decreased gold-induced thrombocytopenia, decreased nonsteroidal antiinflammatory drug-related gastrointestinal hemorrhage, and many others. We believe that the only way to examine these questions is with rigorously controlled, prospective, high-quality. long-term data. Of interest, the data collection process and numbers reported would have easily been sufficient to identify any cases of myelocytic leukemia following cyclophosphamide therapy; the prevalence of that well-recognized complication is obviously much greater than any similar risk that may or may not be present with azathioprine. James F. Fries, MD Stanford Universi/y Medical Center Stanford, C A
Comment on the article by Lockshin To the Editor: We wish to take issue with statements made by Dr. Lockshin in his article dealing with pregnancy and its effects on systemic lupus erythematosus (SLE) (Lockshin MD: Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 32:665-670, 1989). While we applaud the attempt to study patients prospectively, we believe the question of whether pregnancy produces a flare of disease activity in SLE patients can only be answered by studying the same patient for at least 2 years prior to pregnancy, during pregnancy, and 1 year postpartum, thus using the patient as her own control. Lockshin’s investiga-
