Rituximab: rescue therapy in life-threatening complications or refractory autoimmune diseases: a single center experience

Rituximab (RTX) is a chimeric anti-CD20 antibody, approved for rheumatoid arthritis (RA) patients who failed anti-Tumor Necrosis Factor therapy. It has been used occasionally for life-threatening autoimmune diseases (AID). We report our center experience in the use of RTX in life-threatening complications or refractory AID. Clinical charts of patients treated with RTX at our center were reviewed, cases treated for life-threatening complications or refractory AID were analyzed. Acute damage to vital organs such as lung, heart, kidney, nervous system with severe functional impairment were defined as life-threatening complications; treatment failure with high-dose corticosteroids, cyclophosphamide, IVIG, plasmapheresis was defined as refractory autoimmune disease. During the years 2003–2009, 117 patients were treated with RTX, most of them for RA. Nine patients (6 females, mean age 51.5 years, mean disease duration 6.3 years) answered the criteria. The indications were as follows: pulmonary hemorrhage (1 patient with cryoglobulinemic vasculitis, 1 with systemic sclerosis, 1 with ANCA-associated vasculitis), catastrophic anti-phospholipid syndrome (2 SLE patients), non-bacterial endocarditis and pulmonary hypertension (1 patient with mixed connective tissue disease), vasculitis and feet necrosis (1 patient with systemic lupus erythematosus), severe lupus demyelinative neuropathy and acute renal failure (1patient), and severe rheumatoid lung disease with recurrent empyema and pneumothorax (1patient). B cell depletion was achieved in all patients. The median time since starting of complications to RTX administration was 3 weeks (range 2–15 weeks). Complete remission (suppression of the hazardous situation and return to previous stable state) was seen in 7 out of 9 patients. Partial remission (significant improvement) was achieved in the remained. The median time to response was 3 weeks (range 1–8 weeks), mean follow-up 47.2 months (range 6–60 months). A rapid tapering off of steroids was achieved in all patients. Two patients relapsed and were successfully retreated with RTX: the patient with severe RA lung relapsed after 3 years, one of the patients with ANCA-associated pulmonary alveolar hemorrhage relapsed after 10 months. There were no side effects during RTX infusion. Two episodes of serious infections were registered: fatal Gram-negative sepsis 6 months after RTX treatment, and septic discitis 4 months after receiving RTX. RTX serves as a safe, efficient, and prompt rescue therapy in certain life-threatening conditions and resistant to aggressive immunosuppression AID. RTX when administrated at an earlier stage, prevented irreversible vital organ damage, and allowed rapid steroid tapering off in already severe immunodepressed patients.     

Prolonged B Cell Depletion With Rituximab is Effective in Treating Refractory Pulmonary Granulomatous Inflammation in Granulomatosis With Polyangiitis (GPA)

Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22–52) years. Pulmonary nodules (median 4, range 2–6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/μL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P = <0.0001) and largest nodule diameter (P = <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion.     

Recurrent pneumothorax associated with pulmonary nodules after leflunomide therapy in rheumatoid arthritis: a case report and review of the literature

Rheumatoid arthritis (RA) is a multisystem inflammatory disease characterized by destructive synovitis and systemic extraarticular involvement. One of the most common pulmonary manifestations of RA is rheumatoid nodule. Spontaneous pneumothorax also very rare pulmonary finding and could be associated with pulmonary nodules. Antirheumatic drugs, methotrexate, leflunomide (LEF), infliximab and etanercept, were known as risk factors for developing rheumatoid nodule. However, there was no case report of rheumatoid nodule-associated pneumothorax with the use of LEF. We report, first, herein a case of 46-year-old woman with RA who suffered recurrent spontaneous pneumothorax associated with multiple bilateral subpleural cavitary nodules during treatment with LEF. We reviewed the cases of LEF-related pulmonary nodules developed in patients with RA. Thus, we suggested that pneumothorax can be a rare respiratory fatal complication in patients with RA with pulmonary nodules and LEF can be a rare cause of these manifestations.     

A single pulmonary rheumatoid nodule masquerading as malignancy

We present a 54-year-old man, a heavy smoker, with clinical and laboratory evidence of familial hypercholesterolemia and an asymptomatic solitary pulmonary nodule (SPN) increasing in size on follow-up chest X–ray. Laboratory work-up revealed high titers of rheumatoid factor and the presence of acute phase reactants. Because of the patients age and history of smoking, open lung biopsy was performed to rule out malignancy. The biopsy showed histological features compatible with a rheumatoid nodule. Identical features were noted in the histological examination of the subcutaneous nodule. Usually, rheumatoid nodules occur in patients with active, long-standing rheumatoid arthritis (RA) with other extra-articular manifestations. The presence of a single pulmonary rheumatoid nodule as the first manifestation of RA is extremely rare. Histologic proof is often required since pulmonary carcinoma can present an identical clinical and radiological pattern. The diagnostic work-up and the differential diagnosis of an SPN, particularly in a heavy smoker, is a common clinical request and remains a diagnostic challenge.     

Nodular pulmonary opacities in patients with rheumatoid arthritis. A diagnostic dilemma

Nodular opacities are a well-known pulmonary manifestation of rheumatoid arthritis (RA), occurring most often in seropositive men who smoke and have subcutaneous nodules. In the past 15 years two cases of lung carcinoma presenting as pulmonary nodules have been reported in patients with rheumatoid disease. We present seven patients with seropositive RA and subcutaneous nodules who had new pulmonary nodule(s) noted on chest roentgenograms. All but one were current smokers. Carcinoma was found in all patients at bronchoscopy or thoracotomy. Four patients had solitary nodules (one was cavitary); the remaining three patients had multiple bilateral nodules that cavitated in one case. All patients had interstitial abnormality (peribronchial/vascular thickening) with basal predominance in three, and there was evidence of pleural thickening/fluid in three patients. These results strongly suggest that histologic proof of presumed rheumatoid pulmonary nodules be obtained.     

Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease

This study aims to explore the clinical characteristics and risk factors of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). This is a retrospective study of 550 patients with RA. All patients underwent chest high-resolution computed tomography (HRCT) scanning. (1) Two hundred thirty-seven out of five hundred fifty (43.1%) patients with RA were diagnose with ILD. 13.5% ILD occurred before RA onset, 69.6% ILD occurred within 10 years of RA onset, and 16.9% ILD occurred more than 10 years after RA onset. (2) The most common chest CT characteristics of RA-ILD included reticular patterns (57.8%), pleural thickening (57%), ground-glass attenuation (53.2%), followed by interlobular septum thickening, nodules, emphysematous bullae, honeycombing, and bronchiectasis. The proportion of the UIP pattern and NSIP on HRCT was 18.6% and 57.8%. (3) RA-ILD was often associated with other lung lesions, including pleural disease, bronchiectasis, and pulmonary hypertension. (4) the comparisons between RA with ILD and RA without ILD showed that male, smoking, age, disease duration, number of swelling joints, globulin levels, erythrocyte sedimentation rate, C-reactive protein levels, lactate dehydrogenase, the positive rate of rheumatoid factor (RF) and the absolute value of RF, forced vital capacity, forced expiratory volume in 1 s, and carbon monoxide diffusion rate, were statistically different (P < 0.05). Logistic regression analysis showed that age, smoking, elevated lactate dehydrogenase, and RF positive were closely correlated to RA-ILD. RA-ILD occurs more often within 10 years of RA onset and coexists with other lung lesions. The elevated lactate dehydrogenase, RF positive, smoking, and advanced age are closely correlated with RA-ILD.     

Bilateral spontaneous pneumothorax in a patient with pulmonary rheumatoid nodules, secondary infected by Aspergillus

This case report describes a 50-year-old woman with rheumatoid arthritis (RA) in whom nodular opacities were found on chest X-ray. She developed a bilateral spontaneous pneumothorax treated with surgical pleurodesis. Cultures remained negative. Histological examination of specimens confirmed the clinical diagnosis of rheumatoid granulomata. Therefore, corticosteroid therapy was started, after which the nodules decreased slightly in size and inflammatory parameters normalized. Three months later, she presented with respiratory insufficiency based on pulmonary fungus infection. Differential diagnosis between rheumatoid nodules and granulomas caused by Aspergillus is difficult in RA patients with pulmonary nodular lesions; in this case, both complications appeared subsequently.     

Circulating anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis and chronic obstructive pulmonary disease

Anti-cyclic citrullinated peptide (anti-CCP) antibody is highly specific for diagnosing rheumatoid arthritis (RA). Cigarette smoking is a lifestyle and environmental factor associated with anti-CCP production and is strongly associated with chronic obstructive pulmonary disease (COPD). This study assessed levels of anti-CCP antibodies and rheumatoid factor (RF) among patients with RA and COPD. The study sample comprised 63 patients with RA and 70 patients with COPD, all of whom underwent assessment of anti-CCP antibody and RF levels. Testing revealed that 54.2 % of RA patients and 0 % of COPD patients were positive for anti-CCP antibodies. Additionally, 82.5 % of RA patients and 42 % of COPD patients were positive for RF. Among RA patients, levels of anti-CCP antibodies were higher among smokers than among nonsmokers (242.7 ± 128.3 vs. 68.1 ± 112.1, P < 0.001). COPD patients had low titers of RF but were negative for anti-CCP antibodies. The presence of anti-CCP antibodies was a reliable serologic marker in RA diagnosis and was associated with cigarette smoking.     

A double-blind randomized comparative study of triamcinolone hexacetonide and dexamethasone intra-articular injection for the treatment of knee joint arthritis in rheumatoid arthritis

Intra-articular glucocorticoid (GC) injection has been used for more than half a century in the treatment of refractory synovitis in patients with rheumatoid arthritis (RA). There are limited data about the efficacy of intra-articular injection of various preparations of GCs on inflamed joint. The aim of this study was to compare the efficacy and side effects of intra-articular injection of dexamethasone (DEX) and triamcinolone hexacetonide (TH) in the treatment of knee joint arthritis in RA. In a double-blind randomized clinical trial, 70 patients with RA and knee joint arthritis were recruited to the study. Swelled knee joints were injected with 40 mg TH or 8 mg DEX randomly. The primary outcome measures were reduction of knee joint swelling and pain 1 and 3 weeks after joint injection. The secondary outcome measures were relapse of knee arthritis at 2, 4, and 6 months after injection and side effects of intra-articular injection. Difference in the knee circumferences between DEX and TH groups at weeks 1 and 3 was not significant. The average times of pain reduction after injection were 3.4 ± 2.3 and 2.3 ± 1.8 days in TH and DEX, respectively. There were no differences of knee pain between the two groups. Relapse of knee arthritis was occurred in two (6.7 %) and three (9.4 %) patients in the DEX and TH groups, respectively. Intra-articular injection of DEX like TH causes rapid and long-term reduction of knee pain and swelling in patients with RA and is safe.     

Immunoglobulin subtypes predict therapy response to the biologics in patients with rheumatoid arthritis

To analyze the effectiveness of rituximab (RTX) versus alternative TNF antagonists (aTNFs) on rheumatoid arthritis (RA) disease activity in different subgroups of patients and relation with extraarticular manifestations of RA and to assess that RF-subsets have potential as predictors of clinical response to RTX. Patients with RA (n = 40, M/F: 3/37) who received aTNFs at least 6 months with good response (group I; n = 20) or discontinued at least one aTNFs because of the ineffectiveness and subsequently received RTX at least one course (group II; n = 20) were retrospectively evaluated. IgM-, IgA-, IgG-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) levels were measured by ELISA technique. Extraarticular manifestations and radiological scores were also recorded. The mean (SD) age was 51.7 ± 6.5 years in group I and 52.1 ± 6.1 years in group II patients (p > 0.05). The median disease durations were higher in group II than group I [8.0 (2–30) vs. 13 (3–35) years, respectively, p = 0.04]. Presence of RF [13(61.9 %) vs. 20(100 %) p = 0.001] and extraarticular involvement [5(25 %) vs. 13(65 %) p = 0.01] were higher in group II patients. When Ig-RF subgroups analyzed, all subgroup (IgA, IgM, IgG) levels were higher in group II (p = 0.001, p = 0.05, p = 0.001). IgA-RF levels were significantly high in patients with extraarticular involvement (p = 0.04). Association between high RF levels and having extraarticular manifestations in RA patients may largely be attributed to the IgA isotype.     

Patterns of magnetic resonance imaging of the foot in rheumatoid arthritis: which joints are most frequently involved?

To investigate patterns of inflammatory MRI pathologies of the fore- and midfoot in rheumatoid arthritis (RA) and early RA (ERA) and their changes under therapy. In this prospective study, MRI data of the foot of 39 RA patients (29 female, 10 male; age: 54 ± 13 years; disease duration: 35 ± 37 months; baseline DAS28: 3.0 ± 2.0; medication: 29 DMARD, 1 biological, 9 symptomatic or non-specific treatment) were evaluated for synovitis in 314 joints, bone marrow edema and erosions according to RAMRIS criteria in a total of 585 joints. The change in joint pathology intensity was evaluated on follow-up MRI (time of follow-up: 8 ± 4 months) in 25 patients. Inflammation was generally more frequent in the metatarsophalangeal (MTP) joints (221/292; 76 %) than in the proximal metatarsal (47/292; 16 %) and tarsal bones (24/292; 8 %). The overall most frequently involved joints of the foot were MTP 5 (51/292; 18 %) and 1 (49/292; 17 %). Change under therapy was most frequently seen in the MTP 1 joint. Progress of inflammation in the MTP 1 was more frequently found in ERA patients than in patients with established RA (disease duration >12 months) (p = 0.002). In RA, the MTP joints, primarily MTP 5 and 1, are the predominant sites of inflammatory MRI pathologies of the foot. A change of inflammatory activity under therapy can be most frequently noted in the MTP 1 joint. This information might be helpful to improve effectiveness of MRI-controlled therapy approaches and clinical trials.     

Depression is improved when low-dose tacrolimus is given to rheumatoid arthritis patients showing an inadequate response to biologic agents

Purpose

Depression in rheumatoid arthritis (RA) patients is more severe than in healthy people. Herein, we report improved depression in RA patients using biologic agents. We examined whether depression was improved by tacrolimus combination therapy when biologic agents were ineffective.

Method

The study included 13 RA patients who used biologic agents. The following methods were used before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation: the Zung self-rating depression scale (SDS) to evaluate depression state, disease activity score 28/erythrocyte sedimentation rate (DAS28), tender joint counts, swollen joint counts, a patient global assessment to evaluate RA disease activity, and the modified health assessment questionnaire (mHAQ) to evaluate quality of life.

Results

The SDS scores before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation were 45.2 ± 10.6, 44.8 ± 12.8, and 41.6 ± 11.2 (p = 0.047), respectively, indicating significant improvement. The DAS28 was 5.0 ± 1.3 prior to treatment, 3.8 ± 1.3 at 14 weeks, and 3.5 ± 0.9 at 30 weeks, demonstrating significant improvement at both 14 and 30 weeks (p < 0.001). The mHAQ score changed from 0.60 ± 0.45 at baseline to 0.54 ± 0.52 and 0.38 ± 0.43 at 14 and 30 weeks, respectively. The mHAQ score was significantly lower at 30 weeks when compared to baseline (p = 0.013).

Conclusion

Tacrolimus combination therapy does not directly improve depression in RA patients, but it is possible that the observed improvement in depression accompanies the improvement in the secondary failure of RA.     

Identification and prevalence of rheumatoid nodules in the finger tendons using high frequency ultrasonography.

OBJECTIVE: Rheumatoid nodules are classical diagnostic feature of rheumatoid arthritis (RA). The prevalence of rheumatoid nodules in the finger tendons is not known. We determined the prevalence of rheumatoid nodules of finger tendons in patients with RA, using high frequency linear transducers with high resolution ultrasonography. METHODS: The study comprised 54 consecutive patients with RA and 20 controls. Dynamic ultrasound examination of various tendons was performed using real-time equipment, the Apogee 800 ATL, with an 11 MHz linear array transducer. RESULTS: RA nodules were identified in 9 patients (16.66%); their sizes ranged from 0.21 to 0.95 cm (mean 0.35+/-0.12 cm), in 4 cases (7.4%) the nodules were intratendinous. The flexor tendons were affected in the 9 patients. The finger tendon ultrasonography identified RA nodules that had escaped routine clinical detection. CONCLUSION: The ultrasonography technique was valuable in the confirmation of rheumatoid nodule involvement of the finger tendons. The prevalence of rheumatoid nodule in finger tendons was 16.66%. We believe that ultrasonography should be the screening procedure of choice for diagnosis of RA nodules of the fingers.     

Accelerated infusion rates of rituximab are well tolerated and safe in rheumatology practice: a single-centre experience

Due to the possible risk of infusion reactions of rituximab (RTX), a slow infusion rate (total infusion time, 255 min) is suggested for rheumatological use. However, especially in oncology field, accelerated infusion of RTX is reported to be well tolerated and safe. The aim of our study was to evaluate whether accelerated infusion rates of RTX would similarly be safe and tolerable in rheumatoid arthritis (RA) patients and other off-label rheumatological indications. All patients treated with RTX for RA and other autoimmune diseases between May 2011 and January 2012 were recruited to the study. Each treatment course consisted of two RTX 1,000 mg infusions, 2 weeks apart. Total time of the infusion for the first cycle was 255 min. Second and subsequent infusions were administered over 120 min as follows: 0–30 min, 100 mg; 30–60 min, 200 mg; 60–90 min, 300 mg; and 90–120 min, 400 mg. The Clinical Trials Classification of Adverse Events (CTCAE) version 4.3 was used to categorise side effects. The study population comprised 68 patients [F/M, 59:9; mean age, 52.4 (10.6)?years]: 60 with RA, 4 with systemic lupus erythematosus (SLE), 1 with non-Hodgkin’s lymphoma with SLE and 3 with vasculitis. A total of 77 fast infusions were administered. Eleven patients (16.2 %) had taken a fast infusion at the first course. A total of nine patients experienced at least one AE. Seven patients had a reaction on the first infusion (infusion-related reaction (IRR)), two patients on the second infusion and one patient on both infusions. When graded from 1 to 5 according to CTCAE v. 4.3, grade 1 IRRs were observed in a total of seven patients and grade 2 IRR in three patients. In this study of fast infusions, adverse events after RTX were mostly mild and seem to be well tolerated. Faster rituximab infusion times seem to be safe and might be incorporated into routine practice.     

Cost-effective analysis of disease-modifying anti-rheumatic drugs in rheumatoid arthritis

The main objective of the study was to perform the pharmacoeconomic analysis of synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients. A prospective, observational study was conducted in 98 rheumatoid arthritis (RA) patients meeting 2010 Rheumatoid Arthritis Classification Criteria. Treatment-naive RA patients were initiated on synthetic disease-modifying anti-rheumatic drugs (DMARD/s) and followed up for 3 months. Average cost-effectiveness analysis was done by taking Health Assessment Questionnaire Disability Index (HAQ-DI) score as a measure of effectiveness. Out of the 98 RA patients, 15.30% were males and 84.69% females. 80.61% RA patients are seropositive. Majority of the study population patients (55%) were on combination of three synthetic DMARDs and almost a quarter (24.48%) were on combination of two synthetic DMARDs. The mean value of DAS 28 at baseline was 6.07 ± 1.33 and after 3 months treatment, the mean was 3.84 ± 1.11. The mean disability index measured by HAQ-DI was significantly reduced from 1.43 ± 0.71 to 0.81 ± 0.61, p < 0.001, after 3 months treatment. The direct medical cost of treatment of RA per month is 997.05 rupees. The average cost-effectiveness ratio of combination of synthetic DMARDs was 1533.92 rupees. Treatment of RA with synthetic DMARDs controls disease activity and improves disability with reasonable cost of treatment. The majority of the direct medical cost is attributable to cost of medicine and laboratory investigation. Use of quality generic drugs and an early diagnosis would minimize the economic burden on the patient.     

Gutes Ansprechen eines pulmonalen Rheumaknoten auf Rituximab

Pulmonary rheumatoid nodules can be found in over 4% of patients with rheumatoid arthritis. Diagnostically they have to be differentiated from malignant and infectious processes. The present article describes a case of pulmonary rheumatoid nodule which responded well to Rituximab therapy.     

Cost-effectiveness of clinical remission by treat to target strategy in established rheumatoid arthritis: results of the CREATE registry

To analyse the cost-effectiveness, in daily clinical practice, of the strategy of treating to the target of clinical remission (CR) in patients with established rheumatoid arthritis (RA), after 2 years of treatment with biological therapy. Adult patients with established RA were treated with biological therapy and followed up for 2 years by a multidisciplinary team responsible for their clinical management. Treatment effectiveness was evaluated by the DAS28 score. The direct costs incurred during this period were quantified from the perspective of the healthcare system. We calculated the cost-effectiveness of obtaining a DAS28 < 2.6, considered as CR. The study included 144 RA patients treated with biological therapies. After 2 years of treatment, 32.6% of patients achieved CR. The mean cost of achieving CR at 2 years was 79,681 ± 38,880 euros. The strategy of treatment to the target of CR is considered the most effective, but in actual clinical practice in patients with established RA, it has a high cost.     

Clarithromycin in rheumatoid arthritis: the addition to methotrexate and low-dose methylprednisolone induces a significant additive value—a 24-month single-blind pilot study

To compare the efficacy of the addition of clarithromycin (CM) to methotrexate (MTX) and methylprednisolone (MP) in active rheumatoid arthritis (RA). 32 patients with RA consecutively randomized. Control group: sixteen patients treated for 24 months with MTX 10–15 mg i.m. weekly and MP 4–6 mg daily. CM group: sixteen patients treated with MTX 10–15 mg i.m. weekly and MP 4–6 mg daily for 24 months; CM therapy added in the first month (500 mg twice a day for the first 15 days followed by 500 mg a day for the remaining 15 days). Evaluation of the improvement following ACR criteria was performed at months 1 (primary endpoint), 3 and 6. Patients were furthermore observed after 12, 18 and 24 months from the study beginning. At month 1, following ACR70 improvement criteria, we found a significant additive value in CM group (10/16 = 63 % vs 4/16 = 25 %, p = 0.033—chi-square test). After discontinuation of CM, the difference between groups was anymore evident (month 3: CM group 10/16 = 63 % vs control group 9/16 = 56 %). At month 24, 7/16 (44 %) in control group and 12/16 (75 %) in CM group completed the follow-up. The addition of CM to MTX and MP can induce the remission ACR 70 in the majority of RA patients within 4 weeks, while MTX and MP alone need about 3 months to achieve the same result.