Anti-TNF alpha monoclonal antibodies (infliximab) and tuberculosis: apropos of 3 cases

INTRODUCTION: Monoclonal TNF alpha antibodies are a new treatment of severe rheumatoid arthritis. One of the possible side effects is the appearance of opportunistic infections. We report here on three cases of disseminated tuberculosis observed in patients undergoing treatment with infliximab. EXEGESIS: A 45-year-old woman, treated with infliximab, was hospitalised after five infusions for fever and dyspnoea. The exams showed pulmonary and peritoneal tuberculosis. The second case is a 75-year-old woman whose symptoms were fever, cough and cervical adenopathy after three infliximab infusions. Diagnosis was disseminated tuberculosis. The third case is a 59-year-old man who was hospitalised for an infectious syndrome with dyspnoea, after two infliximab infusions. We discovered pulmonary tuberculosis. CONCLUSION: These three cases added to the 68 cases of tuberculosis registered with the treatment of infliximab. This confirms the risk of severe opportunist infectious side effects. TNF alpha is a cytokine which has anti-infectious properties. These tuberculoses are severe and generalized. It is recommended to search for an active or latent tuberculosis before beginning treatment with infliximab, and to check these patients frequently.     

Pulmonary tuberculosis with cerebellar lesion in a patient after anti-TNF-alpha (infliximab) treatment for rheumatoid arthritis]

We report a case of pulmonary tuberculosis in a 51-year-old Japanese woman, who received treatment with infliximab for active rheumatoid arthritis. She had cough and sputum after the second infusion of the drug, small nodular lesions of right lung field and left lower lobe on her chest CT and a small nodular lesion of right cerebellar lobe on her cranial MRI were identified. Mycobacterium tuberculosis was cultured from her sputum. Therefore, we diagnosed her illness as pulmonary tuberculosis with a cerebellar lesion. The patient was treated with anti-tuberculosis drugs and showed marked improvement in lesions of the lung and brain. We considered this case a tuberculosis reactivation after infliximab treatment because of the short interval between the administration of infliximab and the occurrence of tuberculosis, and the complication of extrapulmonary lesion that suggested brain tuberculoma.     

Two cases of respiratory infection complicating treatment with infliximab]

Infliximab, an anti-TNF-alpha agent, is highly effective against rheumatoid arthritis and Crohn's disease. However, respiratory infection can occur as a complication. We report two cases complicated by respiratory infection following administration of infliximab. The first case, a 67-year-old woman with rheumatoid arthritis, developed pneumocystis pneumonia after three courses of infliximab therapy. The second case, a 31-year-old man with Crohn's disease, developed pulmonary tuberculosis after four courses of infliximab therapy. Respiratory complications associated with anti-TNF therapy include infectious diseases such as pneumocystis pneumonia, tuberculosis, and bacterial pneumonia. They often lead a fulminant course, and early diagnosis is essential. The final report of a survey of the initial 5000 cases with rheumatoid arthritis treated with infliximab in Japan was released in April 2006; pulmonary infectious complications included 22 cases of pneumocystis pneumonia, 14 cases of tuberculosis, and 108 cases of bacterial pneumonia. The growing use of anti-TNF therapy might lead to increasing pulmonary complications. Accumulation of similar cases is expected to elucidate the mechanism of the complications and methods for effective prophylaxis.     

肿瘤坏死因子-α拮抗剂引发结核二例分析并文献复习

目的 提高临床医生对肿瘤坏死因子(TNF)-α州拈抗剂治疗引发结核的认识.方法 报道2例类风湿关节炎(RA)患者经TNF-α拮抗剂治疗后发生结核病的临床情况,并复习近年国内外相关文献.结果 病例1在3个月内接受4次英夫利昔3 ms/ks静脉注射治疗后出现右锁骨上淋巴结结核,手术切除及四联抗结核治疗后痊愈.病例2接受依那西普25 mg皮下注射2次/周治疗1.5个月后发生肺结核瘤,手术切除后好转.文献复习显示TNF-α拮抗剂治疗可增加结核的发病率,英夫利昔的致结核作用强于依那西普,发生结核的患者多为老年人,肺外结核及播散性结核的发生率较高.结论 TNF-α拮抗剂治疗可增加结核的发病率,治疗前结核筛查、治疗期间及治疗后监测结核的发生很有必要.     

Tuberculosis pulmonar en relación con adalimumab: estudio de 3 casos

Tumour necrosis factor-alpha antagonist drugs represent a significant advance in the treatment of inflammatory diseases, such as rheumatoid arthritis, spondyloarthropathies, and intestinal inflammatory disease. The increase in tuberculosis with infliximab is known, but there is less data available that specifically associates tuberculosis with adalimumab. We present the cases of 2 patients with rheumatoid arthritis and one patient with ankylopoietic spondylitis on treatment with adalimumab, who developed pulmonary and disseminated tuberculosis despite following the screening and prophylaxis measures recommended in guidelines. We also review the association between treatment with tumour necrosis factor-alpha antagonists and tuberculosis.     

Tuberculous peritonitis during infliximab therapy

Reactivation of tuberculosis is a severe side effect of anti-TNF treatment. Especially extrapulmonary forms of tuberculosis may occur, which are difficult to diagnose. The diagnosis may be obtained by a thorough search for Mycobacterium tuberculosis. We describe two patients who developed tuberculous peritonitis after infliximab therapy that was prescribed for treatment of rheumatoid arthritis. These cases illustrate that tuberculous peritonitis has a nonspecific clinical manifestation and that Mycobacteria can be difficult to find in ascites fluid. For this reason, tuberculostatic therapy has to be started in case of clinical suspicion. Before starting infliximab therapy, the patient must be thoroughly screened for the presence of (latent) tuberculosis.     

Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?

BACKGROUND: Recent studies with infliximab indicate the therapeutic potential of tumour necrosis factor alpha blockade in spondyloarthropathy (SpA). Because defective host defence is implicated in the pathogenesis of SpA, the potential side effects of this treatment due to impact on the antimicrobial defence are a major concern. OBJECTIVE: To report systematically the adverse events seen in a large cohort of patients with SpA treated with infliximab, with special attention to bacterial infections. PATIENTS AND METHODS: 107 patients with SpA were treated with infliximab for a total of 191.5 patient years. All serious and/or treatment related adverse events were reported. RESULTS: Eight severe infections occurred, including two reactivations of tuberculosis and three retropharyngeal abscesses, and six minor infections with clear bacterial focus. One patient developed a spinocellular carcinoma of the skin. No cases of demyelinating disease or lupus-like syndrome were seen. Two patients had an infusion reaction, which, however, did not relapse during the next infusion. Finally, three patients with ankylosing spondylitis developed palmoplantar pustulosis. All patients recovered completely with adequate treatment, and infliximab treatment had to be stopped in only five patients with severe infections. CONCLUSIONS: Although the global safety of infliximab in SpA is good compared with previous reports in rheumatoid arthritis and Crohn's disease, the occurrence of infections such as tuberculosis and retropharyngeal abscesses highlights the importance of careful screening and follow up. Focal nasopharyngeal infections and infection related symptoms, possibly induced by streptococci, occurred frequently, suggesting an impairment of specific host defence mechanisms in SpA.     

Skin reaction to adalimumab

The tumor necrosis factor alpha (TNFalpha) inhibitors etanercept and infliximab have shown good clinical results in the treatment of rheumatoid arthritis and other autoimmune disorders. With these novel fusion proteins, immune-mediated side effects, among them various cutaneous reactions, have been encountered. We report herein the case of an erythema multiforme-like skin reaction to treatment with the monoclonal anti-TNFalpha antibody adalimumab in a patient with rheumatoid arthritis. The reaction occurred after the sixth injection and affected the palms and soles as well as the injection site. Discontinuation of the adalimumab therapy resulted in rapid improvement of the condition. Although this patient was receiving concomitant immunomodulatory therapy with methotrexate and leflunomide, these medications were not discontinued when the reaction developed, and no other potential pathogenetic mechanisms were identified. We believe the reaction is most likely attributable to adalimumab.     

Risk of tuberculosis in a Chinese registry of rheumatoid arthritis and ankylosing spondylitis for tumour necrosis factor‐α antagonists

Aim: To understand the risk of tuberculosis (TB) infection in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) who required tumour necrosis factor‐α (TNF‐α) antagonist treatment. Methods: Patients with RA and AS who were screened for infliximab and etanercept treatment for up to 6 months were entered in a registry between 2003 and 2005. The purified protein derivative (PPD) test and chest anteroposterior and lateral view X‐ray were performed at screening. The risk of TB infection in theses patients was observed during follow up. Results: Among 67 RA patients screened, a positive PPD reaction was found in one patient. Of the 169 AS patients screened, 23 were positive for the PPD reaction, two had pulmonary TB calcinosis and two were diagnosed as having pulmonary TB. The incidence of PPD positive reaction and pulmonary TB calcinosis or active TB in our screened RA and AS patients was significantly lower than that reported in the recent fourth national TB infection rates and prevalence (P < 0.01). Only one patient with RA developed neck lymph node TB 6 months after completion of infliximab infusion. Conclusion: Patients with AS and RA are not at an increased risk of TB infection if screened properly before short course treatment with anti‐TNF‐α agents.     

Case of miliary tuberculosis during treatment with infliximab for rheumatoid arthritis

A 70-year-old woman afflicted with rheumatoid arthritis was consulted another hospital because of fever and abnormality in chest X-ray. She had been treated with methotrexate and infliximab for seven months. She was diagnosed as methotrexate-induced pneumonia, and was administrated large therapeutic doses of corticosteroid, but finding of her chest X-ray exacerbated. Her sputum examination was positive for Mycobacterium tuberculosis complex by nucleic-acid amplification test, and she was diagnosed as miliary tuberculosis. She was treated with INH, RFP, EB, and PZA, and showed good clinical response to treatment. When infliximab is prescribed, we have to bear in mind possible complication of tuberculosis.     

Tonsillar tuberculosis in a rheumatoid arthritis patient receiving anti-TNFalpha (adalimumab) treatment

This case report describes a 61-year-old rheumatoid arthritis patient with an atypical clinical presentation of a sore throat. Because of rheumatoid arthritis refractory to conventional disease-modifying antirheumatic drug therapy, anti-TNFalpha was felt to be indicated, and a screening for tuberculosis was carried out. As the screening for tuberculosis (PPD) was positive, isoniazid was prescribed prophylactically for six months. After eight months of anti-TNFalpha (adalimumab) treatment, he developed tonsillar enlargement and nodular pulmonary lesions. Histopathological and microbial investigations established the diagnosis of tonsillar tuberculosis.     

Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis

We describe 5 patients with rheumatoid arthritis (RA) who developed pulmonary complications following infliximab therapy; 4 patients had preexisting usual interstitial pneumonia. As the pathophysiology of the pulmonary insult is unknown, we advise caution in the use of anti-tumor necrosis factor-alpha therapy in patients with RA with underlying lung disease of sufficient severity to withhold methotrexate treatment.     

Successful resolution of pneumonia developed in a patient affected by Crohn’s disease, rheumatoid arthritis, myasthenia gravis and recurrent uveitis during concomitant treatment with tumour necrosis factor α inhibitors and conventional immunosuppressive drugs

Tumour necrosis factor alpha inhibitors, both infliximab and adalimumab, have been approved for the treatment of both rheumatoid arthritis and Crohn’s disease. A slight increase in the risk of infections in patients receiving immunosuppressants and/or biological agents has been reported. Here, we present the case of a 68-year-old woman affected by Crohn’s disease, myasthenia gravis, recurrent uveitis and rheumatoid arthritis who developed pneumonia during concomitant treatment with biological agents and conventional immunosuppressive drugs.     

A case of bilateral rheumatoid pleuritis successfully treated with tocilizumab

Abstract

The patient was a 77-year-old woman diagnosed as having rheumatoid arthritis (RA) in 1973. She was initiated on infliximab therapy in addition to methotrexate administration in 2009. The therapeutic response decreased after the fifth dose of infliximab, and the patient developed rheumatoid pleuritis due to increased RA disease activity. The therapy was switched from infliximab to tocilizumab, which resulted in amelioration of the arthralgias well as pleuritis. Our results suggest that tocilizumab is an effective treatment alternative for the treatment of rheumatoid pleuritis.     

Delayed response to anti-tuberculosis treatment in a patient on infliximab

The introduction of infliximab, an anti-TNF-alpha agent, in the treatment of rheumatic diseases has offered important therapeutic advances in recent years. The main adverse effect from the usage of this drug is susceptibility to infections, mainly reactivation of latent tuberculosis. We present a 23 year-old male with ankylosing spondylitis, who developed endobronchial and widespread pulmonary tuberculosis, 2 years after initiation of treatment with infliximab. The patient had already been treated for a positive PPD skin test with a 9-month prophylactic course of isoniazid. He was treated with a five drug anti-tuberculosis scheme but he showed an extremely slow therapeutic response with daily high fever, even 4 months after initiation of treatment. Seven months after beginning anti-tuberculosis therapy, bronchoscopy still revealed necrotic and inflammatory tissue at the site of the original lesions. This unusual clinical course of tuberculosis infection was attributed to immunosuppression due to the long-lasting anti-TNF-alpha action of infliximab.     

Successful treatment with intraarticular infliximab for resistant knee monarthritis in a patient with spondylarthropathy: a role for scintigraphy with 99mTc-infliximab

Positive experiences with intraarticular infliximab have been reported in patients with rheumatoid arthritis, ankylosing spondylitis, and Behcet's disease. We used intraarticular infliximab to treat resistant knee monarthritis in a patient with spondylarthropathy. Clinical and laboratory improvement was associated with improvement in scintigraphic findings. This approach is less expensive than intravenous administration of infliximab. We suggest that selection of candidates for this innovative therapy should be guided by anti-tumor necrosis factor alpha scintigraphy.     

Serious liver disease induced by infliximab

Infliximab, a chimeric monoclonal antibody that binds the tumor necrosis factor α (TNFα), is used in the treatment of rheumatoid arthritis (RA) and Crohn’s disease (CD). Previous cases of significant secondary liver disease associated with infliximab treatment have been reported in patients with RA, CD, and psoriatic arthritis. Two additional patients with RA who developed a serious liver disease associated with infliximab treatment are reported here. A 39-year old RA patient was admitted with cholestatic liver disease after 8 months of treatment with infliximab. She had no history of hepatic diseases, exposure to hepatotoxic or illicit drugs, or alcohol abuse. A liver biopsy showed severe ductal proliferation with collapse and enucleation of the hepatocytes. Despite aggressive treatment with oral prednisolone, she developed hepatic failure. On the 45th day, a liver transplant was performed. The second patient, a 54-year old RA patient, was diagnosed with autoimmune hepatitis after 12 infliximab infusions. She fulfilled autoimmune hepatitis type 1 criteria. A liver biopsy disclosed an altered lobulillar structure with chronic inflammation and the formation of collagen bands. She was treated with prednisolone and azatioprine and a complete recovery was noted 1 month later. These cases should alert rheumatologists to the possibility of new adverse reactions (liver injury) associated with the use of TNFα blockers in an autoimmune setting.     

Cerebral tuberculoma in a patient receiving anti-TNF alpha (adalimumab) treatment

We report a case of a cerebral tuberculoma in a 60-year-old woman with rheumatoid arthritis while receiving the anti-tumor necrosis factor alpha monoclonal antibody, adalimumab (Humira), for active disease. MR brain imaging for dyspraxia revealed a left parietal ring-enhancing lesion, which on resection was shown to be a necrotizing granuloma. There were no associated pulmonary lesions, and the patient was systemically well. Sputum and urine cultures were negative for tuberculosis. The patient was treated with anti-tuberculous medications and made an excellent recovery. We consider this to be the first documented case of tuberculosis involving the central nervous system occurring in the setting of adalimumab treatment.     

Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment

Antitumor necrosis alpha agents have been successfully used for the treatment of rheumatoid and seronegative arthritis, Crohn’s disease, psoriasis, and severe cases of vasculitis. Several side effects have been observed in patients receiving these agents including hypersensitivity reactions, infections, drug-induced lupus, or demyelinating syndromes. The presence of peripheral neuropathy has been reported only in isolated cases. We describe two cases of peripheral neuropathy which occurred in patients with rheumatoid arthritis receiving infliximab treatment, one with multifocal motor neuropathy with conduction block and another with axonal sensory polyneuropathy, reversed upon discontinuation of infliximab and intravenous gammaglobulin treatment.