Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease resulting from exposure to inhaled environmental antigens [1] . In the acute form; a definite inciting antigen (IA) is evident and avoidance with/without short course of corticosteroids is sufficient. On the other hand; the chronic form lacks overt and definite IA, in nearly two-thirds of cases i.e., cryptogenic chronic HP (ccHP) [2] . Unfortunately, the course of the latter is insidious and may progress to lung fibrosis simulating idiopathic pulmonary fibrosis (IPF) [3] . Clinical diagnosis can be made by a combination of; 1) history of progressive dyspnea with/without exposure to IA, 2) pulmonary function tests, 3) BAL cytology, 4) HRCT of chest, 5) transbronchial and/or surgical lung biopsy [4] . Methodological differences may account for the variations in reported incidence and prevalence. However, in a recent large-population study, the calculated yearly incidence rate was 1.28 - 1.94 per 100,000 persons and prevalence at 1.67 - 2.71 per 100,000 persons and the mortality of the progressive fibrotic forms were 28% and 52% after 4 and 7 years, respectively [5] . The age of the reported cases was 52 ± 13 years, and cases were four-times more likely to be men than women [6] . Despite avoidance of IA; ccHP fibrosis may progress [7] . Moreover, Corticosteroids were beneficial only in acute HP not ccHP [7] . Other immunosuppressive agents viz. Azathioprine, mycophenolate mofetil (MMF) had marginal benefit in ccHP had less side-effects than Corticosteroids, yet did not improve survival [8] . Reports on Rituximab (R) therapy of ccHP are scarse yet had shown stabilization of disease [9] [10] . In our current study; we prospectively evaluated a new regimen for treatment of ccHP using an induction phase of Prednisone and MMF for 3 months to suppress the disease activity followed by prevention of future relapses with a maintenance yearly therapy with R.

Patients were included if they had the following criteria: 1) progressive respiratory failure without occupational or irritant inciting antigen (IA), 2) spirometric evidence of restrictive lung disease and low diffusion capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC) and 6-minutes-walk (6-MW), 3) absence of chest infections, cardiac disease, primary pulmonary hypertension, collagen vascular diseases, sarcoidosis, lymphoproliferative malignancies, 4) negative past history of drug-induced lung disease, 5) adequate bronchoalveolar lavage (BAL) showing lymphocytosis (>30%), 6) characteristic pulmonary abnormalities, of ccHP, on high-resolution computed tomography (HRCT), 7) lack of allergy to R infusions, 8) adequate pulmonary function tests showing restrictive pattern, 6-months prior to inclusion and on subsequent follow up for >15 months, and 9) adult age group patients without dementia and morbid obesity.

A total of 9 patients were included in the study of which 2 were females. Their; 1) mean age was 64 ± 2 years, 2) prior duration of disease at 93 ± 7 months, and duration of follow up at 26 ± 7 months.

Hypersensitivity pneumonitis (HP) is the third most common interstitial lung disease after idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. However, it remains a challenging condition to diagnose and manage because of its heterogenous clinical, radiologic, histologic and functional features [12] . Clinical diagnosis can be made by a combination of; 1) history of progressive dyspnea with/without exposure to IA, 2) pulmonary function tests, 3) BAL cytology, 4) HRCT of chest, 5) transbronchial and/or surgical lung biopsy [4] . Details include; 1) Common exposures to IA viz. Low-molecular weight chemicals (42.7%) and animal proteins (37.5%), 2) restrictive lung impairment (low FVC and 6-MW) with poor DLCO, 3) BAL cytology should rule out inflammatory, infectious and malignant etiologies and shows > 30% lymphocytosis, 4) HRCT chest abnormalities viz. bilateral, mosaic, ground glass opacities in the middle and lower lung zones (64.6%), ill-defined centrilobular nodules (29.9%) and the sign of air-trapping on expiration (15.6%) in acute/subacute phase while reticulation (45.8%), traction bronchiectasis (21.9%) and honey combing (9.4%) in chronic disease, 5) histological abnormalities on biopsy viz. peribronchiolar diffuse interstitial inflammatory infiltrates, chronic bronchiolitis and peribronchiolar giant cells (with or without non-caseous and non-necrotic granulomas). In our study, none of our patients had identifiable IA i.e., cryptogenic ccHP yet all had typical abnormalities on chest HRCT as per recommendations of CHEST guidelines [5] . Moreover, we added testing for BAL lymphocytosis to satisfy criteria for ATS/JRS/ALAT guidelines [13] . Inflammation in ccHP is mediated by both humoral and cellular mechanisms. The IA activates T-helper lymphocytes followed by activation of B-lymphocytes and subsequent release of antigen-specific immunoglobulin (Ig) G antibodies that leads to accumulation of lymphocytes and formation of granulomas. The fibrotic disease is due to the abnormal repair mechanisms following recurrent alveolar epithelial injury leading to fibroblast activation and proliferation, the accumulation of extracellular matrix, and the eventual destruction of the lung architecture [1] . Hence, treatment of ccHP should start with a short course of aggressive and specific immunosuppressive drugs to halting the active inflammation which was in our patients was evident with 1) disease progression over prior 6 months, and 2) persistent HRCT abnormalities, and 3) high lymphocytic counts in BAL. Subsequently, suppression of activated B-cells, with potent, practical and safe long-term drug, should provide proper maintenance therapy. Hence, in our study we used 2 potent antiproliferative (cytotoxic) agents viz. P & MMF were used simultaneously to treat active ccHP (induction phase) since multiple effector cells are involved. Subsequently, to prevent future relapse, R was used since it is a potent cytotoxic agent to mature B-lymphocytes.

This potent chemo-therapeutic effect is associated with good tolerability profile yet with mild to moderate infusion reactions; hence, it has to be administered slowly over hours, especially the first time [14] . The latter is much less than that observed in treatment of lymphoma which is associated with greater degree of cytokine release [15] . Previously, we reported our experience with the efficacy and safety of yearly Rituximab infusions in many autoimmune diseases [16] [17] [18] [19] . Moreover, the clinical remission induced by R may persist beyond the effect of peripheral B-cell ablation since alteration of memory cells has been reported up to 6 years [20] . The latter character, its long-lasting efficacy (months) and safety were the basis of our protocol for selecting such an agent as a sole maintenance therapy in the second group of our study. Previous studies have shown benefit of R in just stabilization of ccHP [9] [10] . They did not include an essential induction phase to revert the disease which was evident in the dramatic improvement of our patients by the 3^rd month. Previous studies have shown such drugs are effective in treatment of acute inflammatory HP [7] [8] . The effective protocol, in our study, is similar to that used, by our group, in treatment of lupus nephritis [17] . The need for an effective and safe long-term therapy for ccHP is evident with 2 observations. The first is that avoidance of IA may be rewarding in halting early/acute phase of the disease yet is less effective in chronic/fibrotic forms and even can progress despite avoidance of IA [7] . The second is that nearly 2/3 of those with ccHP lack definite IA [2] . These 2 observations indicate that a genetic predisposition to its autoimmune pathogenesis disease is likely. The latter is further supported by the following; for the following reasons; 1) several genetic polymorphisms, including those in major histocompatibility complex class II, have been associated with susceptibility to HP. The MUC5B allele rs35705950 has been associated with a greater extent of radiographic fibrosis, and short telomere length has been associated with worse survival [21] , 2) a diffuse Tc1 immune response of lung parenchyma and airways in patients previously sensitized to one of more than 300 etiologic agents that may favor the HP reaction [22] , 3) Transporter associated with antigen processing (TAP) 1 gene polymorphisms [23] , and 4) several cytokines and chemokines, which are secreted at sites of disease activity, participate in the pulmonary inflammatory responses taking place in the lung of patients with HP [22] . Hence, early long-term safe and effective immunosuppressive therapy is indicated prior to fibrotic stage in susceptible phenotypes in which Nintedanib and Pirfenidone are last resorts otherwise lung transplantation [24] [25] . Finally; the authors acknowledge the limitation of the study with such small number of included patients for such an uncommon disease.

Treatment of ccHP with a 3-month induction phase with P & MFF followed by a maintenance yearly therapy with R is practical, safe and efficacious.

The case was reported according to World Medical Association Declaration of Helsinki.

There was no new or investigational drug added to the patient’s maintenance therapy and they were not subjected to any harmful or injurious investigation.

The authors declare no conflicts of interest regarding the publication of this paper.

El-Reshaid, K., Al-Bader, A., Almutairi, S.S. and Mohamad, S.H.M. (2023) The Beneficial Effect of 3-Month-Induction Therapy with Corticosteroids and Mycophenolate Mofetil Followed by Maintenance Therapy with Yearly Rituximab Infusions as Sole Maintenance Therapy in Cryptogenic Chronic Hypersensitivity Pneumonitis. International Journal of Clinical Medicine, 14, 338-346. https://doi.org/10.4236/ijcm.2023.148029