S E C T I O N
9 Connective Tissue Disorders
89 AMYLOIDOSIS 277.3
Steven P. Dunn, MD
Southfield, Michigan
Jay H. Krachmer, MD
Minneapolis, Minnesota
ETIOLOGY/INCIDENCE
Amyloidosis is a disease complex that results in the accumulation of an amorphous, insoluble, fibrillar protein or aberrantly folded and assembled protein fragments in a variety of tissues. It is readily identified pathologically with polarizing light microscopy by it’s characteristic apple-green birefringence after Congo red staining.
In recent years, the study of amyloid fibrils has led to the classification of amyloid on the basis of the biochemical composition of its subunit proteins. More than 25 fibrillar proteins have now been identified as precursor proteins in amyloidosis. The Nomenclature Committee of Amyloidosis has revised the classification scheme such that all forms are designated by ‘A’ + a suffix that denotes the precursor protein.
Most forms of amyloidosis can be categorized as localized or systemic forms. The two major types of systemic amyloidosis are AL (primary amyloidosis or myeloma-associated amyloidosis) and AA (secondary or reactive amyloid). AL results from deposition of terminal fragments of immunoglobulin kappa or lambda light chains: AA is associated with the acute phase reactant serum amyloid A (SAA) as the precursor protein.
The reported incidence of systemic AL amyloidosis is 1/100,000 persons in Western countries. AA amyloidosis, related to familial Mediterranean fever has a definite ethnic predilection among Sephardic Jews, Armenians, Turks and Arabs having a higher incidence. An increased incidence is seen in patients with tuberculosis, leprosy, anklylosing spondylitis, rheumatoid arthritis and Crohn’s disease. Senile amyloidosis is thought to occur in almost all individuals over the age of 85.
Six types of primary familial amyloidosis have now been described, and they appear to be related most frequently to an abnormality in transthyretin (prealbumin); however, mutations of apolipoprotein A-I, gelsolin, fibrinogen A and lysozyme are also seen. Amyloid deposits resulting from these conditions are usually associated with an autosomal dominant form of inheritance. These forms of amyloidosis are seen in greater frequency among patients originating from Portugal, northern Sweden, Japan, Iceland and Finland.
DIAGNOSIS
Clinical signs and symptoms
Multisystem involvement is characteristic of primary systemic amyloidosis. Progressive peripheral polyneuropathy, cardiomyopathy, and gastrointestinal and skin involvement are seen most frequently. The eye may be involved in a number of ways; linear and veil-like vitreous opacities associated with slowly progressive visual loss, however, are virtually diagnostic of this disease. Discrete, bilateral, yellow-white, xanthoma-like subconjunctival nodules, occasionally with petechiae and hemorrhage, may be the initial findings. Involvement of the lacrimal and parotid glands may produce dryness of the eyes and mouth. Proptosis and external ophthalmoplegia have been attributed to amyloid deposits in the extraocular muscles. Pupillary abnormalities are thought to be due to amyloid neuropathy, or possibly secondary to deposits in the iris sphincter and dilator muscles. Neurotrophic keratitis and glaucoma may also be seen.
Localized, primary amyloidosis may also affect the eye in the form of small pink-red nodules in the lids or conjunctiva. This form of the disease is usually bilateral and affects young adults in their 20s and 30s. A number of forms of primary corneal amyloidosis exist. The most commonly recognized is lattice corneal dystrophy, which has now been broken down into three subtypes based on inheritance pattern and clinical findings.
Type I lattice corneal dystrophy is the classic form; it is autosomal dominant and presents with central, anterior, and midstromal lattice lines and dots and stromal haze. It is not associated with any systemic disorders and typically presents in patients between the ages of 10 and 40. A variant, Avellino dystrophy, has clinical and histologic features of both lattice and granular dystrophies. A mutation in the transforming growth factor beta-induced (TGFBI) gene on chromosome 5q31 is responsible for these conditions.
Type II lattice corneal dystrophy, also known as Meretoja syndrome, is also autosomal dominant. It is actually a manifestation of a form of primary systemic amyloidosis known as Finnish hereditary amyloidosis. It is generally associated with blepharochalasis, bilateral facial nerve palsies, and peripheral neuropathy. Clinically, both peripheral and central lattice lines are found in the anterior stroma. Occasionally, conjunctival and adnexal deposits of amyloid may be seen. Recently, molecular genetics research has isolated a point mutation on the gelsolin gene in patients with clinical findings quite similar to those seen in Finnish hereditary amyloidosis.
Type III lattice corneal dystrophy typically presents in an older age group and is thought to be a recessive disorder characterized by markedly thickened lattice-like lines involving the anterior stroma centrally and paracentrally. On occasion, lattice
161
Disorders9 SECTIONTissue Connective •
lines may extend out to the periphery. This condition is not associated with any systemic abnormality.
Primary gelatinous drop-like keratopathy (GDLD) is a rare amyloid disorder seen most commonly in individuals of Japanese ancestry. The inheritance pattern is thought to be autosomal recessive with a low degree of penetrance. Clinical findings consist primarily of numerous small to moderate-sized subepithelial gelatinous excrescences that give the corneal surface a ‘mulberry’ or ‘toad skin’ appearance. Patients with this disorder tend to present before the age of 20 with symptoms of photophobia, lacrimation, redness, and foreign body sensation. No systemic disorders are associated with this condition. As yet, the precise type of amyloid in gelatinous drop-like keratopathy has not been elucidated. The altered gene responsible for GDLD is M1S1 which is located on the short arm of chromosome 1.
A variety of chronic systemic disorders may be accompanied by secondary systemic amyloidosis. Deposits are found chiefly in the spleen, kidney, and liver. Occasionally, the eyelid may be involved.
Localized secondary amyloidosis may present as clinically detectable deposits in the lids, conjunctiva, and cornea. Clinically unrecognizable microdeposits of amyloid have been found in association with such conditions as basal cell carcinoma of the lid margin, conjunctival intraepithelial neoplasia, and conjunctival sarcoidosis. Microdeposits within the cornea have been seen with retinopathy of prematurity, phlyctenular keratoconjunctivitis, trachoma, trichiasis, keratoconus, and penetrating ocular trauma. Polymorphic amyloid degeneration, a condition typically seen in older patients without a history of ocular disease, is probably a form of primary localized amyloidosis.
Laboratory findings
Corneal lesions have a characteristic clinical appearance, but most other lesions require pathologic evaluation for a definitive diagnosis. Histopathologic features crucial to the diagnosis of amyloidosis include:
●Distinctive fibrillar ultrastructure;
●Staining of pathologic specimens with Congo red;
●Apple-green birefringence under polarized light.
●The observation that transthyretin is synthesized predominantly by the liver has led to liver transplantation or combined liver-kidney transplantation as therapy for this disease (familial amyloid polyneuropathy).
Local
●Localized disease is usually managed surgically; excision is performed for diagnostic as well as therapeutic reasons.
●The disease, however, has a strong tendency to recur.
●Reduced vision commonly leads to penetrating keratoplasty by the fourth or fifth decade in patients with lattice dystrophy.
●Keratoplasty may also be helpful in patients with gelatinous drop-like dystrophy and diffuse familial amyloidosis.
●Polymorphic amyloid degeneration does not usually require therapy.
●Total vitrectomy appears to be the treatment of choice for amyloid patients with dense vitreous opacities that interfere with vision.
PRECAUTIONS
There is a high incidence of recurrent amyloid deposition following surgery. This is particularly important when cosmetic surgery is planned. Regrafting or repeat vitrectomy is an option available to the patient with recurrent corneal and vitreal amyloidosis and visual deterioration.
COMMENTS
Localized amyloid deposits are by far the most common form of ocular amyloidosis. In some cases, amyloid deposits involving the eye may actually be an early localized manifestation of a generalized amyloidosis. This is particularly true with eyelid and vitreal amyloid deposits. The possibility that these deposits may be associated with an underlying disease process or immunologic abnormalities must always be considered.
Differential diagnosis
●Orbital tumors.
●Conjunctival sarcoidosis.
●Epibulbar rheumatoid nodulosis.
●Foreign body granuloma.
●Conjunctival lymphoid infiltrates (lymphomas, MALTomas).
●Multiple myeloma and cryoglobulin corneal deposits.
TREATMENT
Systemic
●All patients in this group require a thorough evaluation that includes the search for an underlying cause of the amyloidosis (i.e. inflammatory or neoplastic).
●Because some amyloid fibrils have an immunologic origin, therapeutic trials using melphalon, prednisone, colchicines or a combination of these have been tried.
●Chemotherapy with the iodinated anthracycline 4′-iodo-4′ deoxydoxorubicin has also demonstrated some clinical benefit in patients with immunocyte-derived (AL) amyloidosis.
REFERENCES
Brunt EM, Tiniakos DG: Metabolic storage diseases: amyloidosis. Clin Liver Disease 8:915–930, 2004.
Doughman DJ: Ocular amyloidosis. Surv Ophthalmol 13:133–142, 1969.
Falk RH, Comenzo RL, Skinner M, et al: The systemic amyloidoses. N Engl J Med 337:898, 1997.
Gorevic PD, Muroz PE, Gorgone G, et al: Amyloidosis due to a mutation of the gelsolin gene in an American family with lattice corneal dystrophy, type II. N Engl J Med 325:1780–1785, 1991.
Henderson JW: Orbital tumors. Philadelphia, WB Saunders, 1973: 602–608.
Hitchings RA, Tripathi RC: Vitreous opacities in primary amyloid disease: a clinical, histochemical, and ultrastructural report. Br J Ophthalmol 60:41–54, 1976.
Knowles DM II: Amyloidosis of the orbit and adnexae. Surv Ophthalmol 19:367–384, 1975.
Mannis MJ, Krachmer JH, Rodrigues MM, et al: Polymorphic amyloid degeneration of the cornea: A clinical and histopathologic study. Arch Ophthalmol 99:1217–1223, 1981.
Meretoja J: Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal systems: a progressive, unrecognized, heritable syndrome. Ann Clin Res 1:310–312A, 1969.
162
90 BEHÇET DISEASE 136.1
Ilknur Tugal-Tutkun, MD
Istanbul, Turkey
ETIOLOGY/INCIDENCE
Behçet disease is a multisystem inflammatory disorder of unknown etiology. Although it has a worldwide distribution, it is more prevalent in the Mediterranean area, the Middle East and the Far East. Behçet disease is closely associated with HLAB51 in endemic areas. Microbial antigens have long been proposed as the triggering factors. An antigen-driven specific inflammatory response superimposed on enhanced innate immune functions is implicated in the pathogenesis of vascular endothelial dysfunction and occlusive vasculitis.
COURSE/PROGNOSIS
Age of onset is usually around the end of the third decade. The frequency of ocular involvement is 50–70%. The disease has a relapsing remitting course. Male patients have a younger age of onset, more severe disease and a higher risk of visual loss compared to female patients. The risk of visual loss at 10 years has been estimated to be 30% in males and 17% in females. However, visual prognosis has improved in the last decade due to an earlier and more aggressive use of immunosuppressive therapy. Furthermore, a trend to milder disease and better visual outcomes has been reported from Japan. Mortality is associated with severe neurological, intestinal and cardiovascular involvement.
TREATMENT
Ocular
In patients with only anterior uveitis topical corticosteroids and mydriatic agents are used.
Local corticosteroid injections, including intravitreal injection of triamcinolone acetonide may be required for the treatment of severe panuveitis attacks and/or cystoid macular edema.
Systemic
Corticosteroids are used for the treatment of uveitis attacks. Long-term immunosuppressive therapy is required in order to prevent recurrences in patients with posterior segment involvement. Colchicine does not have a proven effect on eye disease. Azathioprine (2 mg/kg/day) and cyclosporin A (5 mg/kg/day) have been found to be effective in controlled trials. Combination of cyclosporin A with antimetabolites is more effective than monotherapy. Ciclosporine is best avoided in patients with neuro-Behçet due to its potential neurotoxicity. Tacrolimus (FK506) (0.10–0.15 mg/kg/day) has an immunologic activity and side-effect profile similar to cyclosporin A. Alkylating agents (cyclophosphamide and chlorambucil) have been reserved for cases refractory to initial treatment with cyclosporin A and antimetabolites. Encouraging results have been recently reported on the use of new biologic agents, including interferon alfa and anti-TNF alfa monoclonal antibody, infliximab, in patients with uveitis resistant to conventional agents. Interferon alfa-2α is administered as monotherapy at an initial dose of 6 million units per day subcutaneously. The response rate has been reported to be 94%. Infliximab infusions (5 mg/kg) are usually given at 8-week intervals following a loading dose. In open trials, it has been shown to have a rapid antiinflammatory effect and reduce the frequency of uveitis attacks.
DIAGNOSIS
Clinical signs and symptoms
The diagnosis of Behçet disease is clinical. Systemic manifestations include recurrent oral and genital ulcers, skin lesions, arthritis, thrombophlebitis, arterial aneurysms, intestinal ulcers and neuropsychiatric symptoms. The typical form of ocular involvement is bilateral nongranuomatous panuveitis and retinal vasculitis. Explosive uveitis attacks and spontaneous remissions mark the disease course. Ocular findings include cells and flare in the anterior chamber, hypopyon, diffuse vitritis, retinal vasculitis, retinitis, retinal hemorrhages, retinal vein occlusions, macular edema, papilledema, papillitis, and rarely conjunctival ulcers, episcleritis, scleritis and keratitis.
COMPLICATIONS
Cataract, posterior synechiae, secondary glaucoma, maculopathy, optic atrophy, retinal atrophy and scarring, disc or retinal neovascularizations, retinal detachment and phthisis.
COMMENTS
The etiopathogenesis of Behçet disease has not been elucidated yet. There are individual variations in disease course and severity. There is no single therapeutic regimen uniformly effective in all patients with Behçet disease.
Laboratory findings
There are no laboratory findings specific for Behçet disease. HLA-B51 positivity may help to support a clinical diagnosis. Patients may have skin hyperreactivity, i.e. a positive pathergy test, defined as >2 mm erythema occurring 48 hours after a skin prick by a sterile needle. Patients may have leukocytosis, high erythrocyte sedimentation rates and high C-reactive protein levels during active disease.
Differential diagnosis
HLA-B27-associated uveitis, sarcoidosis, syphilis, viral retinitis and endophthalmitis.
REFERENCES
Kötter I, Gunaydin I, Zierhut M, et al: The use of interferon alfa in Behçet disease: review of the literature. Semin Arthritis Rheum 33:320–335, 2004.
Ohno S, Nakamura S, Hori S, et al: Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet’s disease with refractory uveoretinitis. J Rheumatol 31:1362–1368, 2004.
Okada AA: Drug therapy in Behçet’s disease. Ocul Immunol Inflamm 8:85–91, 2000.
Sfikakis PP, Kaklamanis PH, Elezoglou A, et al: Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behçet disease. Ann Intern Med 140:404–406, 2004.
Disease Behçet • 90 CHAPTER
163
Disorders9 SECTIONTissue Connective •
Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al: Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol 138:373–380, 2004.
Verity DH, Wallace GR, Vaughan RW, et al: Behçet’s disease: from Hippocrates to the third millennium. Br J Ophthalmol 87:1175–1183, 2003.
Yoshida A, Kawashima H, Motoyama Y, et al: Comparison of patients with Behçet’s disease in the 1980s and 1990s. Ophthalmology 111:810–815, 2004.
tagmus in 32%, oscillopsia in 15%, Ménière -like symptoms without hearing loss in 4%, and hearing loss in only 4%. Ocular symptoms and signs develop first in 50% of patients, vestibuloauditory complaints develop first in 25% of patients and both occur within 1 month of each other in 25% of patients. In 50% of patients, an antecedent upper respiratory illness has occurred.
91 COGAN SYNDROME 370.52
Rex M. McCallum, MD
Durham, North Carolina
ETIOLOGY/INCIDENCE
Cogan syndrome is a rare clinical entity of unknown etiology and unknown incidence first described by David Cogan, MD, in 1945. It occurs primarily in young adults and has an average age of onset of 28.6 in 47 patients evaluated at the National Institutes of Health and Duke University Medical Center.
Laboratory findings
●Leukocytosis in 75%:
●Neutrophilia in 50%;
●Mild eosinophilia in 17%.
●Relative lymphopenia in 25%.
●Anemia in 33%.
●Thrombocytosis in 30%.
●Erythrocyte sedimentation rate (ESR) of >20 in 75%.
●Rheumatoid factor ≤1 : 80 in 10%.
●Elevated cerebrospinal fluid protein or white blood cell count or both in 25% of patients studied.
●Audiogram almost always abnormal:
●Most pronounced at the extreme frequencies;
●Relative sparing of the midrange frequencies.
●Short-increment sensitivity index testing and brain stem auditory evoked potential studies suggest cochlear disease.
●Caloric testing is abnormal to absent in 96% of patients.
COURSE/PROGNOSIS
The primary ocular manifestation, interstitial keratitis, is either acute and recurrent or chronic. It may vary in intensity from day to day and from eye to eye. In the acute stages, conjunctival hyperemia and patchy white infiltrates of the subepithelium are noted more often than deep or midcorneal stroma. Corneal infiltrates are more prominent at the periphery. Epithelial defects can be seen. In the later stages, corneal vascularization and opacity may be noted, typically at the corneal periphery. Posterior uveitis and other forms of ocular inflammation are rarely found.
Ocular outcome is excellent, with only 6% of patients having a visual acuity greater than 20/30 in either or both eyes. Auditory outcome, however, is less good; permanent loss of hearing occurs commonly, depending on use of oral corticosteroids. In patients not treated with oral corticosteroids, 17% had an auditory threshold of <60 db, whereas 81% of patients who were treated with oral corticosteroids had an auditory threshold of <60db. The primary systemic complication is the development of aortitis or large-vessel (Takayasu-like) vasculitis or both in 10% to 12% of patients.
Differential diagnosis
●Infections:
●Syphilis, congenital or acquired;
●Lyme disease;
●Chlamydia;
●Virus.
●Vasculitis:
●Polyarteritis nodosa;
●Wegener granulomatosis;
●Temporal arteritis;
●Takayasu arteritis.
●Rheumatic diseases:
●Rheumatoid arthritis;
●Relapsing polychondritis;
●Behçet disease.
●Toxins:
●3-Methyl-1-pentyn-3-yl acid phthalate (Whipcide);
●Cobalt;
●Desferioxamine.
●Others:
●Sarcoidosis;
●Vogt–Koyanagi–Harada syndrome;
●Ménière disease with eye inflammation.
DIAGNOSIS
Clinical signs and symptoms
The syndrome is characterized by inflammatory eye disease, typically nonsyphilitic interstitial keratitis, and vestibuloauditory dysfunction, typically Ménière-like disease. Presenting ocular complaints are ocular discomfort (90%), redness (79%) and photophobia (68%). Ocular examination reveals interstitial keratitis in 72%, conjunctivitis in 34%, iritis in 32%, and episcleritis/scleritis in 28%. The presenting vestibuloauditory symptoms are vertigo (85%), sudden hearing loss (79%), sudden nausea and vomiting (70%), tinnitus (53%), ataxia (45%) and gradual decrease in hearing (17%). Vestibuloauditory features include Ménière-like symptoms with hearing loss in 92%, nys-
TREATMENT
Systemic
●Systemic corticosteroids are rarely necessary to control the symptoms and signs of acute interstitial keratitis, but they may be appropriate for the rare patient with posterior ocular inflammation associated with Cogan syndrome.
●Systemic corticosteroids are immediately indicated in the treatment of hearing loss associated with Cogan syndrome. Hearing loss may respond by showing significant improvement.
●An initial trial of daily oral corticosteroid at a dose of 1 to 2 mg/kg/day of prednisone-equivalent therapy is instituted.
164
This can be started in divided doses for 3 to 5 days in severely symptomatic patients, with subsequent consolidation to a single daily morning dose.
●If hearing improves, then the patient should undergo a taper to a qd regimen over 4 to 6 days followed by a tapering of corticosteroids over the subsequent 6 to 8 weeks, while clinical status is being monitored.
●Clinical parameters such as auditory symptoms, ESR, ocular inflammatory disease and audiogram establish the efficacy of therapy.
●If no response is noted in 2 to 3 weeks, the patient should be rapidly tapered off corticosteroids and a trial of other immunosuppressive therapy, such as methotrexate, azathioprine, cyclosporin A, or cyclophosphamide, should be considered. The effectiveness of immunosuppressive treatment has never been established.
●Immunosuppressive therapy is effective for ‘steroid sparing’ in some patients whose hearing loss responds to corticosteroid therapy but who cannot be tapered to an acceptably low dosage or who suffer unacceptable side effects from steroids.
●Salt restriction, diuretic therapy, or both may be effective in the treatment of hearing fluctuation secondary to cochlear hydrops. Diuretics commonly used are hydrochlorothiazide and chlorthalidone.
Ocular
●Topical 1% mydriatic solution or ointment is appropriate for the management of acute anterior uveitis.
●Topical corticosteroids, such as 1% prednisolone applied every 1 to 2 hours during the acute stages of inflammation and then tapered after appropriate response, are indicated for the control of corneal and ocular inflammation.
●Between flares of interstitial keratitis, no topical ophthalmic therapy is necessary.
Surgical
●The most common indication for ocular surgery is the development of cataracts that interfere with visual acuity. Cataracts may require interventions at an early stage secondary to the deafness commonly present and the resulting need to lip-read and use sign language.
●Cochlear implants have been used successfully in deaf patients with Cogan syndrome.
●Aortic valve replacement should be considered in patients with hemodynamically significant aortic insufficiency. Aortitis can make this technically challenging, and the cardiovascular surgeon should be made to understand the inflammatory nature of the problem. Ideally, the operation should occur after a period of treatment that is deemed effective.
●Vascular bypass procedures may be indicated to prevent ischemic tissue damage. Operating at a time of active inflammation can complicate such procedures; therefore, if possible, surgery should be postponed until effective treatment has been established.
Other
●Patients with progressive hearing loss should be strongly encouraged to learn lip-reading and sign language.
●Patients should be educated about the symptoms and signs of large-vessel inflammatory disease (e.g. limb claudication, pulse changes, new aortic insufficiency murmur and different blood pressure in each arm) and taught to
seek medical attention if these signs and symptoms occur.
COMPLICATIONS
Corticosteroids are potentially dangerous medications, so patients must be closely supervised and given individualized dosages in accordance with the severity of the Cogan syndrome, the therapeutic response, the side effects evident (if any), and the anticipated duration of therapy. Corticosteroids should be given as a single morning dose except for a few days when starting therapy or in the case of an active inflammatory exacerbation of the disease. The lowest possible dose that controls the specific manifestation or manifestations being treated should be sought and used for the shortest amount of time possible. Alternate-day regimens can commonly provide therapeutic benefit while minimizing significant side effects. Tapering of corticosteroids should be performed gradually and cautiously while monitoring the clinical parameters of disease activity. The side effects of systemic corticosteroids are numerous and potentially serious, and they occur commonly in patients receiving prolonged therapy. Side effects include osteoporosis, susceptibility to infections, weight gain, rounded facies, cataracts, increased intraocular pressure, proximal muscle weakness, easy bruisability, striae and psychosis. Given the potential for side effects, trials of corticosteroid therapy should be administered only when therapeutic goals, therapeutic endpoints and criteria for monitoring have been established at the onset of the trial. The best indicators for corticosteroid therapy are hearing loss and the development of inflammatory vascular complications.
The most common side effects of hydrochlorothiazide and chlorthalidone are volume and potassium depletion. Potassium replacement therapy may be necessary. Unusual side effects of these drugs include leukopenia, allergic problems and rashes.
Cyclosporine is a potent immunosuppressive agent that profoundly inhibits normal T cell activation and function, in part through effects on interleukin-2. The primary clinically significant toxic manifestations of cyclosporin A are renal dysfunction and hypertension. Therefore, careful monitoring of both blood pressure and renal function is necessary. Baseline serum creatinine should be established prior to the institution of therapy, with monthly monitoring to follow. Serum creatinine should not be allowed to rise more than 30% above the baseline. If this occurs, the cyclosporin A dose should be decreased by 50 mg/day, and repeat monitoring should be undertaken in 2 weeks. The usual starting dose of cyclosporin A is 2.5 to 5.0 mg/kg/day in two equally divided doses 12 hours apart. Doses of ≤5.0 mg/kg/day and trough levels of ≤400 mg/mL may be associated with less renal dysfunction. Other potential cyclosporine side effects include hirsutism, infection, tremulousness, hypomagnesemia, hepatic dysfunction, nausea and lymphoreticular neoplasm.
Cyclophosphamide, an alkylating agent, is also a potent immunosuppressive drug. Potential side effects include bone marrow suppression, hemorrhagic cystitis, bladder cancer, nausea, infection (particularly herpetic), gonadal dysfunction, pulmonary and hepatic reactions, and lymphoreticular neoplasm. The drug is usually given each morning with breakfast and forced intake of 1 to 2 L of fluid between breakfast and lunch to minimize the risk of bladder irritation. Initial doses are 2 mg/kg/day unless severe inflammatory vascular disease
Syndrome Cogan • 91 CHAPTER
165