A case report of extra-articular manifestation of rheumatoid arthritis: Rheumatoid nodules in lungs.

Rheumatoid arthritis is a systemic inflammatory disorder primarily affecting joints but not limited to the joints alone. Extra-articular manifestations involve skin, ocular, gastrointestinal, pulmonary, cardiac, renal, neurological, and hematological systems. Among them, skin manifestations (20%) are most common, presenting as nodules on the extensor surfaces of the upper and lower extremities. In rare cases these nodules can also be detected within the heart and lungs. Interestingly, rheumatoid nodules are often seen in patients on leflunomide, methotrexate, or tumor necrosis factor-alpha antagonists. Nevertheless, definitive diagnosis requires a histopathological analysis. In this case report, we presented a 49-year-old male patient with a relatively short period of disease activity leading to rheumatoid nodules in the lungs. Considering the ongoing COVID-19 pandemic and that tuberculosis was still endemic in Kazakhstan, achieving the definite diagnosis was challenging. Initial imaging study revealed bilateral polysegmental pneumonia. The tests for COVID-19 and pulmonary tuberculosis were negative. A follow-up chest computed tomography scan had signs of disseminated lung lesions of unknown origin. Lung biopsy showed a morphological picture of productive granulomas characteristic for tuberculosis. However, at the second look, typical scarring granulomas typically seen in rheumatoid nodules were observed.

A case of rheumatoid arthritis with multiple lung rheumatoid nodules successfully treated with tofacitinib.

Sporadic cases of rheumatoid nodules (RNs) in the lung during treatment with tumour necrosis factor (TNF) inhibitors have been reported, but no treatment has been established. Here, we report a case of symptomatic lung RNs refractory to abatacept (ABT) and intravenous cyclophosphamide (IVCY) that improved with tofacitinib (TOF) treatment. A 75-year-old Japanese woman with a 10-year history of rheumatoid arthritis (RA) presented with a cough and haemoptysis during treatment with etanercept (ETN). Radiographic examinations revealed multiple nodules that were diagnosed as lung RNs via biopsy. The ETN was discontinued and ABT followed by IVCY was introduced; however, neither was sufficiently effective against the lung RNs. Thereafter, TOF was started and the lung RNs improved rapidly. The precise mechanisms that induce RNs during treatment with TNF inhibitors are unknown. Cytokines (IL-23 and IL-6) are suspected to be involved. TOF may be a reasonable strategy for treating symptomatic lung RNs.

Granulomatous Cutaneous Drug Eruptions: A Systematic Review.

BACKGROUND: Granulomatous drug eruptions are rare entities, where granuloma formation occurs as an attempt to contain an exogenous or endogenous inciting agent. Granulomatous drug eruptions may be localized to the skin or may include major systemic involvement, and their characteristics depend both on the properties of the causative irritant and host factors. Because of the overlapping features amongst noninfectious granulomatous diseases, granulomatous drug eruptions are challenging to diagnose and distinguish both histologically and clinically. OBJECTIVE: The objective of this article is to provide a review and summary of the current literature on the five major types of cutaneous granulomatous drug eruptions: interstitial granulomatous drug reaction, drug-induced accelerated rheumatoid nodulosis, drug-induced granuloma annulare, drug-induced sarcoidosis, and miscellaneous presentations. METHODS: A systematic review was conducted through PubMed using the search terms "granulomatous drug eruption" and "cutaneous" or "skin". English full-text studies that included human subjects experiencing a cutaneous reaction comprising granulomatous inflammation as the direct result of a drug were included. Of 205 studies identified, 48 articles were selected after a full-text review. Evidence was evaluated using the Tool for evaluating the methodological quality of case reports and case series. RESULTS: Polypharmacy and a prolonged lag period from drug ingestion to rash onset may create diagnostic challenges. Ruling out tuberculosis is imperative in the endemic setting, particularly where anti-tumor necrosis factor therapy is the presumed cause. Interstitial granulomatous drug reactions and granuloma annulare are often localized to the skin whereas accelerated rheumatoid nodulosis and sarcoidosis may sometimes be associated with systemic features as well. Granulomatous drug eruptions typically resolve on discontinuing the offending medication; however, the decision for drug cessation is dependent on a risk-benefit assessment. In some situations, supplementation of an additional agent to suppress the reaction may resolve symptoms. In some cases, granulomatous drug eruptions may be pivotal in the successful outcome of the drug, as in cases of melanoma treatment. In all situations, the decision to continue or withdraw the drug should be carefully based on the severity of the eruption, necessity of continuing the drug, and availability of a suitable alternative. CONCLUSIONS: Granulomatous drug eruptions should always be considered in the differential diagnosis of noninfectious granulomatous diseases of the skin. Further research examining dose-response relationships and the recurrence of granulomatous drug eruptions on the rechallenge of offending agents is required. Increased awareness of granulomatous drug eruption types is important, especially with continuous development of new anti-cancer agents that may induce these reactions. CLINICAL TRIAL REGISTRATION: PROSPERO registration number CRD42020157009.

Prevalence and clinical significance of extra-articular manifestations at diagnosis in the ESPOIR cohort with recent-onset arthritis.

OBJECTIVES: The aim of this study was to determine the prevalence and clinical significance of extra-articular manifestations (EAMs) at inclusion into a cohort of patients with recent-onset arthritis consistent with rheumatoid arthritis (RA). METHODS: The ESPOIR cohort included patients aged 18 to 70 years who had a definitive or probable diagnosis of RA. Symptoms consistent with EAMs were collected at baseline. We divided the patients into two groups, with vs. without baseline EAMs. We looked for associations linking the presence of EAMs at baseline to patient and disease characteristics at baseline and 5 years later, as well as to diagnostic certainty after 2 years. The analyses were adjusted for multiple comparisons using the Benjamini-Hochberg procedure to control the false discovery rate. RESULTS: Of 798 patients, 330 (41.4%) had at least one symptom consistent with EAM at baseline, with the most common being sicca syndrome (28.4%) and Raynaud's phenomenon (17.3%). The EAM+ group had a higher mean baseline DAS-28 value (5.3 ± 1.3 versus 5.0 ± 1.3; corrected p value = 0.005) compared to the EAM- group. The final diagnosis did not differ between the two groups. After 5 years, the EAM+ group had significantly higher values for the tender joint count (3.9 ± 6.4 versus 1.8 ± 3.3, corrected p value = 0.005) and swollen joint count (1.3 ± 2.8 versus 1.1 ± 2.3, corrected p value =0.0005) compared to the EAM- group. CONCLUSION: EAMs, particularly sicca syndrome and Raynaud's phenomenon, are very common in patients with early arthritis consistent with RA. In this population, several parameters reflecting disease activity were higher among patients with EAMs, at baseline and after 5 years.

Occurrence of pulmonary rheumatoid nodules following biological therapies.

In rheumatoid arthritis (RA), disease activity is generally determined by the joint involvement, but the treatment outcome is often influenced by extra-articular manifestations. Authors present a 74-year-old female patient's case history, who was treated with seropositive RA. Marked disease activity was observed even following combined traditional disease-modifying antirheumatic drug (DMARD) treatment (disease activity score in 28 joints (DAS28) = 6.6). Therefore, the patient received TNF-α antagonist therapy. Golimumab was administered subcutaneous (SC) once monthly which resulted in significant improvement in both clinical and laboratory signs (DAS28 = 3:43). However, the follow-up chest x-ray indicated multiple intrapulmonary foci and enlarged lymph nodes. Biopsies and histology excluded malignancy; rheumatoid nodules were confirmed. Anti-TNF therapy was discontinued and tocilizumab treatment was initiated. The IL-6 receptor inhibitor suppressed arthritic activity, and 2 months later, the follow-up chest x-ray showed a regression of chest nodules. Our cases, as well as reports from other centers, suggest that TNF blockade may induce rheumatoid nodulosis and the use of alternative biologics may be feasible as further treatment of RA.

[Complications and systemic manifestations of rheumatoid arthritis]. / Complications et atteintes systémiques de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA), in addition to the traditional joint damage can affect all organs as a systemic disease. Extra-articular manifestations of RA are highly variable ranging from rheumatoid nodules (most common) to rheumatoid vasculitis presenting a significant morbidity and mortality (49% at 5 years). With the new algorithms of treatment (earlier) and the use of biologics, the incidence of severe extra-articular manifestations decreases. Regarding the treatment of rheumatoid vasculitis, rituximab looks promising. RA also increases cardiovascular risk and the risk of osteoporosis. It is therefore important to identify these risks and, if appropriate, treat them. Collaboration with the general practitioner is essential in this situation.

Vasculitis of the gallbladder in early rheumatoid arthritis.

Vasculitis secondary to rheumatoid arthritis (RA) usually occurs in patients with high circulating titres of rheumatoid factor and established, chronic disease. Vasculitis of the gallbladder causing acute cholecystitis is an extremely rare manifestation of rheumatoid vasculitis. To our knowledge, this is the first case in which vasculitis occurred early in the course of disease. We report the case of a localised gallbladder vasculitis in a 74-year-old, newly diagnosed male patient with RA. He presented with acute abdominal pain, a history of constitutional symptoms and a 1-week history of polyarthritis of his wrist and hands. Cholecystitis was diagnosed clinically and radiologically and he underwent a laparoscopic cholecystectomy. Histopathology of the gallbladder confirmed cholecystitis and gallstones but in addition found small vessel vasculitis and rheumatoid nodules. This case illustrates that rheumatoid vasculitis can occur early in the onset of RA. Additionally, although rare, the gallbladder can be a site of localised rheumatoid vasculitis.

Pulmonary rheumatoid nodules: presentation, methods, diagnosis and progression in reference to 5 cases.

Rheumatoid nodules are a rare manifestation of lung disease associated with rheumatoid arthritis (RA). Their emergence and evolution in the course of the disease is variable. The diagnosis of pulmonary rheumatoid nodules may be suggested if they have a typical appearance in an appropriate clinical context, but an accurate diagnosis cannot be made based only on imaging tests. It is recommended to follow nodules and may be necessary to histologically differentiate them from tumors.

Good clinical response to methotrexate treatment in a patient with fibroblastic rheumatism.

Fibroblastic rheumatism (FR) is a rare disease first described by Chaouat (in Rev Rhum Mal Osteoartic 47:345-351, 1980) and is characterized by a combination of rheumatologic and dermatological manifestations. Rheumatologic features are symmetrical polyarthralgias with joint stiffness, associated with cutaneous nodules and sclerodactyly. Histology shows an increased number of fibroblasts and a marked dermal fibrosis. A large number of treatments have been tried, but all of them have shown an unpredictable effect on FR. We report a Brazilian case of FR showing a good clinical response to methotrexate treatment. This drug may be considered an effective treatment in FR.

Relationship between arterial dysfunction and extra-articular features in patients with rheumatoid arthritis.

Systemic inflammation may be a common process that underpins both atherosclerosis and extra-articular features (ExRA) of rheumatoid arthritis (RA). We evaluated the relationship between ExRA and arterial dysfunction in 114 consecutive patients with RA (82% women) without overt arterial disease aged 40-65 years. A trained research nurse undertook 'SphygmoCor' pulse wave analysis (PWA) using radial applanation tonometry to measure the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, msec) of aortic wave reflection. Assessment included fasting blood sample, patient questionnaire and medical record review. Mean differences were adjusted for age, sex, mean blood pressure, smoking pack-years, fasting cholesterol, Stanford HAQ score and erythrocyte sedimentation rate. Mean age was 54 (SD 7) and median RA duration 10 (IQR 4-17) years. There was a trend for arterial dysfunction (higher AIX%; lower RWT) to increase as the number of ExRA features rose, but no difference in AIX% (-0.5, 95%CI -2.8 to 1.8, P = 0.65) or RWT (0.3 ms, 95%CI -3.6 to 4.2, P = 0.86) between 'any ExRA' and 'no ExRA'. Arterial dysfunction was not associated with the presence of rheumatoid nodules, Sjogren's syndrome or carpal tunnel syndrome. Our study was too small to determine whether severe ('Malmo') ExRA (vasculitis, pericarditis, episcleritis) was truly associated with a higher AIX% (3.8, 95%CI -2.3 to 9.9, P = 0.22) and lower RWT (-5.5 ms 95%CI -13.1 to 2.1, P = 0.16). While arterial dysfunction may be associated with the number of ExRA features and severe ExRA, it does not appear to be associated with other ExRA features.

Extraarticular manifestations in Turkish patients with rheumatoid arthritis: impact of EAMs on the health-related quality of life in terms of disease activity, functional status, severity of pain, and social and emotional functioning.

The aim of our study was to investigate extraarticular manifestations (EAMs) in Turkish patients with rheumatoid arthritis (RA) and also assess the impact of EAMs on various health-related quality of life (HRQoL) domains, including physical, social, emotional, mental functioning, and bodily pain. A total of 150 patients were included in the study. EAMs were identified clinically. Pulmonary involvement was confirmed by using pulmonary function tests (PFT) and high-resolution computed tomography (HRCT), atlantoaxial subluxation by cervical spine X-rays. Peripheral neuropathy, rheumatoid nodules, and Sicca symptoms were picked up on clinical examination. Peripheral neuropathy was also confirmed by electroneurophysiologic studies. Patients were evaluated by Rheumatoid Arthritis Quality of Life (RAQoL), and Short form-36 (SF36). The quadrivariate Disease Activity Score- 28 (DAS28) was used for measuring disease activity. Functional status was evaluated by using the Stanford Health Assessment Questionnaire (HAQ). The severity of pain was documented by using 10-cm Visual Analog Scale-Pain (VAS-pain). EAMs were observed in 50 patients (33.3%). These were pulmonary involvement (28.7%), rheumatoid nodules (14.7%), Sicca Syndrome (8%), peripheral neuropathy (2.7%), and atlantoaxial subluxation (0.7%), respectively. It was not recorded any statistically significant difference in HAQ, DAS28, VAS-pain, and RAQoL scores between the patient groups with and without EAMs. Patients with EAMs scored significantly lower in physical functioning, role-physical, and role-emotional subgroups of SF36 (P < 0.01). Presence of EAMs is not directly associated with disease activity and functional status, but influences negatively HRQoL including physical and emotional functioning.

[Leishmaniasis and rheumatoid nodulosis in a patient with HIV infection]. / Leishmaniasis y nodulosis reumatoide en paciente con infección por el virus de la inmunodeficiencia humana.

We describe the case of a 44-year-old homosexual man diagnosed with HIV infection and visceral leishmaniasis. He presented nodules on the dorsum of the hands. Histological study of one of the nodules revealed necrobiotic palisading granulomas with abundant Leishmania amastigotes within the histiocytes and in the adjacent extracellular space. Tissue and peripheral blood cultures were positive for Leishmania infantum, zymodeme MON-24. A biopsy of healthy skin did not reveal the presence of Leishmania. A diagnosis of rheumatoid nodulosis with Leishmania was made and treatment was started with intravenous liposomal amphotericin, leading to slight improvement. We believe that the presence of the parasite within the nodules was the result of its dissemination during visceral leishmaniasis in an immunocompromised patient with HIV infection, and that the Leishmania did not have an etiological role in the appearance of the nodules. We present the first case of the association between Leishmania and rheumatoid nodulosis.

MRI and pathological findings of rheumatoid meningitis.

Rheumatoid meningitis (RM) is one of the most severe complications of rheumatoid arthritis. The mortality rate of RM is relatively high and diagnosis can be difficult. We present an 80-year-old woman who was diagnosed with microscopic findings of RM after analysis of biopsy specimens taken from a brain lesion. MRI scanning revealed meningeal enhancement in the brain, and the pathological findings were those of meningeal lymphocytic infiltration, vasculitis and rheumatoid nodules. RM is a treatable disease and in this patient RM was diagnosed on the basis of biopsy findings.