Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient.

A major obstacle to the treatment of hyperuricemia in patients allergic to allopurinol is the limited availability of suitable, equally effective, alternative, urate-lowering drugs. Conventional uricosuric drugs, including probenecid and sulfinpyrazone, are recommended for allopurinol- intolerant patients with gout and "underexcretion" hyperuricemia who have normal renal function and no history of nephrolithiasis. Therapeutic options in those in whom traditional uricosuric drugs are contraindicated, ineffective, or poorly tolerated include slow oral desensitization to allopurinol and cautious administration of oxipurinol. Allopurinol desensitization is useful particularly in those who have failed other treatment modalities. If available (as in Europe, South Africa, and Japan), benzbromarone may be tried in patients with gout and mild-to-moderate renal insufficiency. Recombinant urate oxidase can be used in the short-term prophylaxis and treatment of chemotherapy- associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders. Hyperuricemia and gout occur with increased frequency in cyclosporine-treated allograft transplant recipients. The management of gout in these patients is complicated by two main factors: cyclosporine-induced renal impairment, and interactions with medications used to preserve the allograft.

Efficacy and safety of desensitization to allopurinol following cutaneous reactions.

OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.

Recent advances in the management of adult myositis.

Standard drug therapy of adult polymyositis, dermatomyositis and inclusion body myositis includes high-dose corticosteroids and cytotoxic drugs (methotrexate, azathioprine (AZA) and cyclophosphamide). Recent data are in favour of the early introduction of a cytotoxic or immunomodulating drug in addition to corticosteroid therapy. In patients with corticosteroid- and cytotoxic-resistant myositis, promising novel approaches to management include: iv. megadose pulse methylprednisolone combined with cytotoxic drugs, combination therapy with both methotrexate and AZA, cyclosporin, tacrolimus, fludarabine and iv. immunoglobulin (IVIG). Recent advances in the understanding of the role of cytokines and complement, in the pathogenesis of myositis, have led to preliminary therapeutic trials of three biological agents: etanercept, infliximab and anti-C5 monoclonal antibody.

Paraneoplastic rheumatic syndromes.

Malignant neoplasms are associated with a wide variety of paraneoplastic rheumatological syndromes. Among these, hypertrophic osteoarthropathy, carcinoma polyarthritis, dermatomyositis/polymyositis, and paraneoplastic vasculitis are the most frequently recognized. Other less known associations are based upon a smaller number of reported patients, and include fasciitis, panniculitis, erythema nodosum, Raynaud's syndrome, digital gangrene, erythromelalgia and lupus-like syndromes. Musculoskeletal manifestations of malignancy may coincide, follow or antedate the diagnosis of cancer, or herald its recurrence. The clinical course generally parallels that of the primary tumour, and treatment of the underlying malignancy often results in regression of the rheumatic disorder. Awareness that cancer can cause certain non-metastatic symptoms is important for early diagnosis and treatment of an occult neoplasm. Rheumatic manifestations suggesting a hidden cancer include: rapid onset of an unusual inflammatory arthritis clubbing or diffuse bone pains in a patient 50 years of age or older, chronic unexplained vasculitis, refractory fasciitis, Raynaud's syndrome unresponsive to vasodilator therapy, rapidly progressive digital gangrene or Lambert-Eaton myasthenic syndrome. Management consists of control of the underlying cancer and symptomatic treatment of the rheumatic syndrome with non-steroidal anti-inflammatory drugs or corticosteroids.

Primary cutaneous B cell lymphoma during methotrexate therapy for rheumatoid arthritis.

A patient with rheumatoid arthritis developed a reversible, primary cutaneous, large B cell lymphoma during prolonged methotrexate (MTX) treatment. Regression of the skin lesions after discontinuation of the drug suggested a close relationship to MTX. Increased clinical awareness, discontinuation of MTX, and close observation are important in the initial management of this rare lymphoproliferative disorder.

What is new about crystals other than monosodium urate?

Recently, attention has focused on the effects of weather conditions and seasonal changes on the incidence of acute microcrystalline events. Acute gout attacks are more frequent during the spring, but seasonal variations in the incidence of acute pseudogout attacks are less clearly defined. Genetic analysis of two unrelated families with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease showed linkage to the short arm of chromosome 5p. Several recent reports show CPPD crystal disease occurring in association with Gitelman syndrome, the hypocalciuric-hypomagnesemic variant of Bartter syndrome. Two signaling pathways, protein kinase C and adenyl cyclase, modulate generation of extracellular pyrophosphate by porcine cartilage chrondrocytes. These transduction mechanisms may provide potential targets for the treatment of CPPD crystal deposition disease. A controlled clinical trial showed ultrasound therapy to be beneficial in the treatment of symptomatic chronic calcific tendinitis of the shoulder. There is evidence that apatite crystals may contribute to cartilage damage in osteoarthritis and that therapeutic interventions to prevent the formation and biologic effects of the crystals may potentially retard the progression of the osteoarthritic process.

Skeletal muscle infarction in diabetes mellitus.

OBJECTIVE: To analyze the risk factors, clinical features, and methods of diagnosis of diabetic muscle infarction (DMI). METHODS: Three patients with diabetes mellitus (DM) and skeletal muscle infarction were studied, and 49 additional cases reported in the English literature (Medline database search) were reviewed. RESULTS: Review of all 52 patients with DMI revealed a number of typical features: equal sex distribution; mean age 41.5 years (range 19-81 yrs); a number of risk factors [long duration of DM (mean 15.2 yrs), poor control and microvascular diabetic complications (neuropathy, retinopathy, nephropathy) (94%), and insulin dependent type I DM (77%)]; a characteristic clinical presentation with painful diffuse muscle swelling (100%); and sometimes a muscle mass (44%), predilection for quadriceps (62%), hip adductors (13%) and leg muscles (13%), elevated serum creatine phosphokinase (47%), abnormal sonograms (81%), abnormal magnetic resonance image (MRI) findings (100%), typical histopathologic findings of a muscle infarct (100%) (ultrastructural evidence of microangiography in one patient); and a tendency toward spontaneous resolution although recurrences are common (51%). CONCLUSION: Skeletal muscle infarction is a rare complication of long standing, poorly controlled DM associated with multiple end organ microvascular sequelae. Increased clinical awareness is important for early recognition, particularly in a diabetic patient presenting with a painful thigh or leg swelling. MR imaging is the diagnostic study of choice, and in the appropriate clinical setting, may obviate the need for a muscle biopsy.

Fibroblastic rheumatism: clinical and histologic evolution of cutaneous manifestations.

Correlation of the clinical manifestations of a patient with fibroblastic rheumatism with sequential skin biopsy findings revealed an early inflammatory stage with cutaneous nodules, patchy erythematous skin lesions, polyarthritis, dermal lymphomonocytic infiltrates, and fibroblastic and myofibroblastic proliferation, followed by a chronic stage with sclerodactyly, joint ankylosis, deformities and dense dermal fibrosis. Treatment of this rare disorder in its early active stages may prevent the development of incapacitating joint sequelae.

Gout in the elderly. Clinical presentation and treatment.

Gout in the elderly differs from classical gout found in middle-aged men in several respects: it has a more equal gender distribution, frequent polyarticular presentation with involvement of the joints of the upper extremities, fewer acute gouty episodes, a more indolent chronic clinical course, and an increased incidence of tophi. Long term diuretic use in patients with hypertension or congestive cardiac failure, renal insufficiency, prophylactic low dose aspirin (acetylsalicylic acid), and alcohol (ethanol) abuse (particularly by men) are factors associated with the development of hyperuricaemia and gout in the elderly. Extreme caution is necessary when prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute gouty arthritis in the elderly. NSAIDs with short plasma half-life (such as diclofenac and ketoprofen) are preferred, but these drugs are not recommended in patients with peptic ulcer disease, renal failure, uncontrolled hypertension or cardiac failure. Colchicine is poorly tolerated in the elderly and is best avoided. Intra-articular and systemic corticosteroids are increasingly being used for treating acute gouty flares in aged patients with medical disorders contraindicating NSAID therapy. Urate-lowering drugs are indicated for the treatment of hyperuricaemia and chronic gouty arthritis. Uricosuric drugs are poorly tolerated and the frequent presence of renal impairment in the elderly renders these drugs ineffective. Allopurinol is the urate-lowering drug of choice, but its use in the aged is associated with an increased incidence of both cutaneous and severe hypersensitivity reactions. To minimise this risk, allopurinol dose must be kept low. A starting dose of allopurinal 50 to 100mg on alternate days, to a maximum daily dose of about 100 to 300mg, based upon the patient's creatinine clearance and serum urate level, is recommended. Asymptomatic hyperuricaemia is not an indication for long term urate-lowering therapy; the risks of drug toxicity often outweigh any benefit.

Mycobacterium xenopi arthritis.

Osteoarticular Mycobacterium xenopi infections are very rare. We describe a patient with dermatomyositis and isolated shoulder arthritis due to M. xenopi. The diagnosis was delayed for 7 months; only 2 of 5 interval joint aspirates grew M. xenopi. The infection responded well to triple antituberculous therapy.

Managing problem gout.

For the management of acute gouty arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. In recent years, the use of colchicine has declined because of its frequent adverse reactions, and its reduced efficacy when administered more than 24 hours after onset of an acute attack. Intra-articular corticosteroid therapy (e.g. methylprednisolone acetate) is indicated for the treatment of acute mono or oligoarticular gouty arthritis in aged patients, and in those with co-morbid conditions contraindicating therapy with either NSAIDs or colchicine. Oral corticosteroids (e.g. prednisone), and both parenteral corticotrophin (ACTH) and corticosteroids (e.g. intramuscular triamcinolone acetonide) are valuable, relatively safe alternate treatment modalities in those with polyarticular attacks. For the treatment of hyperuricaemia and chronic gouty arthritis, allopurinol is the preferred urate-lowering drug. Its toxicity in elderly individuals, those with renal impairment, and in cyclosporine-treated transplant patients can be minimised by adjusting the initial dose according to the patient's creatinine clearance. In those experiencing cutaneous reactions to allopurinol, cautious desensitisation to the drug can be achieved using a schedule of gradually increasing doses. The therapeutic usefulness of uricosuric drugs is limited by the presence of renal impairment, occurrence of intolerable side-effects, or concomitant intake of salicylates. They are particularly indicated in patients allergic to allopurinol and in those with massive tophi requiring combined therapy with both allopurinol and a uricosuric.

Intradermal urate tophi.

OBJECTIVE: To analyze the clinical features and identify risk factors associated with the development of intradermal urate tophi. METHODS: Six patients (5 men and 1 woman, mean age 59.8 yrs) with intradermal tophi were studied between 1987 and 1996. RESULTS: Intradermal urate crystal deposits appeared as small, superficial, pustule-like, whitish lesions. All patients experienced superimposed inflammatory episodes with increasing pain, swelling, and erythema of the intradermal tophi. In one patient, the lesions were associated with a peculiar skin hyperpigmentation. Five had intermittent liquefaction and ulcerations of the lesions with drainage of white chalky matter from which monosodium urate crystals were recovered. Mean pre-treatment serum urate was 570.6 mumol/l (range 496-720). Risk factors for gout and intradermal tophi included renal failure in all 6, hypertension and chronic diuretic therapy in 4, and one patient each with alcohol abuse, chronic low dose acetylsalicylic acid, myeloma, and a positive family history. CONCLUSION: Intradermal urate tophi with superimposed inflammatory episodes, intermittent ulcerations, and possibly pigmentary changes, are rare skin manifestations of chronic tophaceous gout. Renal insufficiency, hypertension, and chronic diuretic use are factors associated with the development of hyperuricemia and gout in these patients.

Current therapy of acute microcrystalline arthritis and the role of corticosteroids.

The management of acute gout, and other acute microcrystalline arthritides, can be difficult in aged patients, and in those with multiple medical illnesses contraindicating therapy with either nonsteroidal anti-inflammatory drugs or colchicine. Intra-articular corticosteroid therapy is particularly useful for the treatment of acute mono-or oligo-articular micro-crystalline synovitis in these patients. Oral corticosteroids (e.g., prednisone), and both parenteral corticotrophin (adrenocorticotrophic hormone) (ACTH) and corticosteroids (e.g., triamcinolone acetonide, methylprednisolone acetate), are useful alternate treatment modalities in those patients with acute polyarticular attacks. Although ACTH has demonstrated comparable clinical efficacy to corticosteroids in the treatment of acute micro-crystalline events, corticosteroids are preferred by many physicians for many reasons: administration can be oral, dose can be regulated precisely, effectiveness does not depend on adrenocortical responsiveness, and incidence of certain side effects, such as hypertension and fluid overload, is lower.

Acute gouty synovitis associated with "urate milk".

OBJECTIVE: To analyze the clinical features of acute gouty synovitis associated with thick, milky white, "chalky," urate laden synovial effusions, and to investigate the effects on synovial white blood cell (WBC) counts when leukocyte-rich rheumatoid effusions are incubated with a urate packed milky synovial fluid. METHODS: Five patients (all men, mean age 70.8 years) with acute gouty synovitis (acute arthritis in 3, acute bursitis in 2) associated with "urate milk" were studied between 1993 and 1996. RESULTS: Synovial effusions were thick, "chalky," and appeared "milky" white. The fluids were packed with monosodium urate (MSU) crystals, which sedimented upon standing, leaving a clear supernatant containing a few MSU crystals. The presence of massive amounts of MSU crystals and crystal clumps interfered with accurate determination of synovial WBC counts. Four fluids showed "a few leukocytes," and one a WBC count of 6750/mm3 with 91% neutrophils and several intraleukocytic crystals. Four patients had subcutaneous tophi. Of the risk factors associated with development of gout, the most frequent was ethanol abuse, in 4 and possibly all 5 patients. Incubation of leukocyte-rich rheumatoid synovial effusions with urate laden knee fluid from Patient 5 produced a greater reduction in synovial WBC counts compared to controls. CONCLUSION: Milky white synovial effusions containing massive quantities of urate crystals (referred to as "urate milk") may rarely occur in the setting of acute gouty arthritis or bursitis. Ethanol abuse appears to be a risk factor associated with the development of hyperuricemia and gout in these patients.

Gouty arthritis in nodal osteoarthritis.

OBJECTIVE: To analyze the clinical features and identify factors associated with the development of gouty arthritis in nodal osteoarthritis (OA). METHODS: Thirty-two consecutive patients (21 women and 11 men, mean age 75.8 years) with both nodal OA and crystal proven acute gout and/or tophi of distal/proximal interphalangeal (DIP/PIP) joints were studied between 1986 and 1994. RESULTS: Tophi of DIP and/or PIP joints were present in 29 (90%) patients; alone in 9 and together with acute DIP or PIP gouty arthritis in 20. Three patients had acute DIP or PIP gouty episodes but no digital tophi. Mean pretreatment serum urate was 614.9 +/- 163.2 (range 422-1088 mumol/l). Risk factors for gout included diuretic use (81%), renal failure (59%), hypertension (66%), alcoholism (22%), prophylactic low dose ASA (20%), and a positive family history (16%) of patients. CONCLUSION: The coexistence of gouty arthritis in nodal OA is important to recognize and treat, particularly in elderly women with renal failure, hypertension, or cardiac failure who are receiving longterm diuretic therapy.

Calcium pyrophosphate crystal deposition disease and other crystal deposition diseases.

"Tumoral" calcium pyrophosphate dihydrate (CPPD) crystal deposition in the ligamentum flavum is rare and can lead to compression myeloradiculopathy in the cervical spine and to spinal canal stenosis in the lumbar spine. CPPD crystal deposition disease is rarely associated with Bartter's syndrome and hypomagnesemia. Intramuscular corticotropin has proved effective in the treatment of acute episodes of pyrophosphate arthritis in patients with multiple medical illnesses in whom nonsteroidal anti-inflammatory drugs are contraindicated. IgG binding to CPPD crystals enhances neutrophil activation (by increasing intracellular cytoplasmic calcium levels) and seems to play a greater role in pyrophosphate than in urate crystal-induced inflammation. Transforming growth factor-beta 1 stimulates intracellular pyrophosphate generation by articular chondrocytes. The effect is inhibited by probenecid, an anion transport blocker, through interfering with the active transport of intracellular pyrophosphate to cartilage matrix where crystals form. Calcific tendinitis associated with underlying cortical bone erosions is an uncommon manifestation of apatite crystal deposition disease. Closed-needle tidal irrigation proved beneficial in two patients with Milwaukee shoulder syndrome. Two patients with nodular subcutaneous cholesterol crystal deposition are described.

Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis.

OBJECTIVE: To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model. METHODS: OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals. RESULTS: At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPD-injected and noninjected, showed embedded synovial cartilage shards. CONCLUSION: The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease.